OXYMETHYLENE ARYL COMPOUNDS FOR TREATING INFLAMMATORY GASTROINTESTINAL DISEASES OR GASTROINTESTINAL CONDITIONS

COMPOSES D'ARYLE D'OXYMETHYLENE POUR LE TRAITEMENT DE MALADIES GASTRO-INTESTINALES INFLAMMATOIRES OU DE TROUBLES GASTRO-INTESTINAUX

English Abstract

Use of oxymethylene aryl GPRl 19 agonists, and optionally DPP IV inhibitors and optionally metformin, for the treatment of inflammatory gastrointestinal diseases or gastrointestinal conditions involving malabsorption of nutrients and/or fluids are provided.

French Abstract

L'invention porte également sur l'utilisation d'agonistes de GPRl 19 d'aryle d'oxyméthylène, et facultativement d'inhibiteurs de DPP IV et facultativement de metformine, pour le traitement de maladies gastro-intestinales inflammatoires ou de troubles gastro-intestinaux impliquant une mauvaise absorption de nutriments et/ou de fluides.

Claims

What is Claimed
1. A method of treating an inflammatory gastrointestinal disease or a
gastrointestinal
condition involving malabsorption of nutrients and/or fluids in a patient in
need
thereof, the method comprising administering to the patient a therapeutically
effective amount of a compound of Formula (I),
Image
wherein,
D is selected from the group consisting of O, S, and NR8,
X, Y, and Z are independently selected from the group consisting of O, N, NR8,
S, and CR3
and at least one of X, Y, and Z is O, N, NR8, or S;
J, K, T, and U are each independently selected from the group consisting of C,
CH, and N;
the subscript p is an integer of from 0 to 4;
the subscript q is an integer of from 0 to 4;
R1 is a member selected from the group consisting of H, C1-10alkyl, C1-
10substituted alkyl, C3-
7cycloalkyl, C2-10alkenyl, C2-10alkynyl, X1-CORa,-X1-CO2Ra,
-X1-CONRaRb, -SO2Ra, a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-

membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo
group,
aryl group and heteroaryl group is optionally substituted with from 1 to 4
substituents
independently selected from halo, C1-10alkyl,
C1-10substituted alkyl, C3-7cycloalkyl, C2-10 alkenyl, C2-10alkynyl, aryl,
heteroaryl, -CN, -NRaCORb, -NRaCONRaRb, -NO2, -ORa, -NRaRb, -CORa,
-CO2Ra, -CONRaRb, -S(O)mRa, -NRaS(O)2Rb, and -SO2NRaRb, or optionally Ra and
Rb
are combined to form a 4-, 5- or 6-membered ring, and X1 is selected from the
group
consisting of a bond, C2-6alkene, C2-6alkyne, -C(O)-, and
-C(O)-(CH2)1-4-, wherein the aliphatic portions of X1 are optionally
substituted with one
to three members selected from halogen, C1-4alkyl, C1-4substituted alkyl and
C1-
4haloalkyl;
each R2 is a member independently selected from the group consisting of
halogen,
164

C1-5 alkyl, C1-5substituted alkyl, C3-7cycloalkyl, -CORa, -CO2Ra, -CONRaRb, -
ORa,
-NRaRb, -NRaCORb, -SORaRb, -SO2Ra and -SO2NRaRb, and wherein when the
subscript
q is 2 and R2 is alkyl or substituted alkyl, the two R2 members can optionally
cyclize to
form a ring;
R3 is a member selected from the group consisting of hydrogen, halogen, C1-
4alkyl, and C1-
4haloalkyl;
each R7 is independently selected from the group consisting of halo, C1-
10alkyl,
C1-10 substituted alkyl, C3-7cycloalkyl, C2-10alkenyl, C2-10alkynyl, -CN, -
NO2,
-ORa, -NRaRb, -CORa, -CO2Ra, -CONRaRb, -NRaCORb, -NRaCO2Rb,
-NRaCONRaRb, -S(O)mRa, -NRaS(O)mRb, -SO2NRaRb, a 4- to 7-membered heterocyclo
group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said
heterocyclo
groups, said aryl and heteroaryl groups are optionally substituted with from
one to four
substituents independently selected from halo, oxo, C1-4 alkyl, C1-4
haloalkyl, C3-7
cycloalkyl, -CN, -NO2, -ORa, -NRaRb, -CORa,
-CO2Ra, -CONRaRb, -NRaCORb, -NRaCO2Rb, -NRaCONRaRb, -S(O)mRa,
-NRaSO2Rb, and -SO2NRaRb and wherein the subscript m is an integer of from 0
to 2, or
optionally Ra and Rb are combined to form a 4-, 5- or 6-membered ring;
R8 is a member independently selected from the group consisting of hydrogen,
C1-4alkyl, and C1-4haloalkyl;
and each Ra and Rb is independently selected from the group consisting of
hydrogen, C1-10
alkyl, C1-10haloalkyl, C3-10cycloalkyl, heterocyclyl, C2-10alkenyl,
C2-10alkynyl, aryl, 5- to 6-membered heteroaryl and arylC1-4alkyl; and wherein
the
aliphatic portions of each of said Ra and Rb is optionally substituted with
from one to
three members selected from the group consisting of halo, -ORn, -OCORn,
-OC(O)N(Rn)2, -SRn, -S(O)Rn, -S(O)2Rn, -S(O)2N(Rn)2, -NRnS(O)2Rn,
-C(O)N(Rn)2, -C(O)Rn, -NRnC(O)Rn, -NRnC(O)N(Rn)2, -CO2Rn, -NRnCO2Rn,
-CN, -NO2, -N(Rn)2 and -NRnS(O)2N(Rn)2, wherein each Rn is independently
hydrogen
or an unsubstituted C1-6 alkyl;
and wherein the aryl and heteroaryl portions are optionally substituted with
from one to three
members selected from
halogen, -ORm, -OC(O)N(Rm)2, -SRm, -S(O)Rm, -S(O)2Rm, -S(O)2N(Rm)2,
-NRmS(O)2Rm, -C(O)N(Rm)2, -C(O)Rm, -NRmC(O)Rm, -NRmC(O)N(Rm)2,
165


-CO2R m, -NR m CO2R m, -CN, -NO2, -N(R m)2 and -NR m S(O)2N(R m)2, wherein
each R m is
independently hydrogen or an unsubstituted C1-6 alkyl;
or a pharmaceutically acceptable salt or ester thereof; and
wherein the molecular weight of said compound is less than 1200.
2. The method of claim 1, wherein said compound of Formula I is selected
from the
group consisting of the compound of example 52, 76, 77, 95, 148, 162, 170,
171, 182,
184, 185, and 195, or a pharmaceutically acceptable salt thereof.
3. The method of claim 2, wherein said compound of Formula (I) is
Image
or a pharmaceutically acceptable salt thereof.
4. The method of any one of claims 1-3, further comprising concurrently or
sequentially
administering a DPP-IV inhibitor to the patient.
5. The method of claim 4, wherein said DPP-IV inhibitor is selected from
the group
consisting of sitagliptin, vildagliptin, denagliptin, saxagliptin,
linagliptin, alogliptin,
R1438, NVP DPP728, PSN9301, P32/98, NN-7201, ALS2-0426, gemigliptin,
anagliptin, teneligliptin, trelagliptin, dutogliptin, and omarigliptin.
6. The method of claim 4 or claim 5, wherein said DPP-IV inhibitor is
selected from the
group consisting of sitagliptin, vildagliptin, saxagliptin, linagliptin,
gemigliptin,
anagliptin, teneligliptin, trelagliptin, omarigliptin, and alogliptin.
7. The method of any one of claims 1-6, wherein the inflammatory
gastrointestinal
disease or the gastrointestinal condition involving malabsorption of nutrients
and/or
fluids is selected from the group consisting of short bowel syndrome (SBS),

166


inflammatory bowel disease, Crohn's disease, ulcerative colitis, volvulus, and

necrotizing enterocolitis.
8. The method of any one of claims 1-7, further comprising concurrently or
sequentially
administering metformin to the patient.
9. A method of treating short bowel syndrome in a patient in need thereof,
the method
comprising administering to the patient a therapeutically effective amount of
a
compound of Formula (I),
Image
wherein,
D is selected from the group consisting of O, S, and NR8,
X, Y, and Z are independently selected from the group consisting of O, N, NR8,
S, and CR3
and at least one of X, Y, and Z is O, N, NR8, or S;
J, K, T, and U are each independently selected from the group consisting of C,
CH, and N;
the subscript p is an integer of from 0 to 4;
the subscript q is an integer of from 0 to 4;
R1 is a member selected from the group consisting of H, C1-10alkyl, C1-
10substituted alkyl, C3-
7cycloalkyl, C2-10alkenyl, C2-10alkynyl, -X1-COR a, -X1-CO2R a,
-X1-CONR a R b, SO2R a, a 4- to 7-membered heterocyclo group, aryl and a 5- to
10-
membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo
group,
aryl group and heteroaryl group is optionally substituted with from 1 to 4
substituents
independently selected from halo, C1-10alkyl,
C1-10substituted alkyl, C3-7cycloalkyl, C2-10 alkenyl, C2-10alkynyl, aryl,
heteroaryl, -CN, -NR a COR b, -NR a CONR a R b, -NO2, -OR a, -NR a R b, -COR
a,
-CO2R a, -CONR a R b, -S(O)m R a, -NR a S(O)2R b, and -SO2NR a R b, or
optionally R a and R b
are combined to form a 4-, 5- or 6-membered ring, and X1 is selected from the
group
consisting of a bond, C2-6alkene, C2-6alkyne, -C(O)-, and
-C(O)-(CH2)1-4-, wherein the aliphatic portions of X1 are optionally
substituted with one

167

to three members selected from halogen, C1-4alkyl, C1-4substituted alkyl and
C1-
4haloalkyl;
each R2 is a member independently selected from the group consisting of
halogen,
C1-5 alkyl, C1-5substituted alkyl, C3-7cycloalkyl, -CORa, -CO2Ra, -CONRaRb, -
ORa,
-NRaRb, -NRaCORb, -SORaRb, -SO 2Ra and -SO 2NRaRb, and wherein when the
subscript
q is 2 and R2 is alkyl or substituted alkyl, the two R2 members can optionally
cyclize to
form a ring;
R3 is a member selected from the group consisting of hydrogen, halogen, C1-
4alkyl, and C1-
4haloalkyl;
each R7 is independently selected from the group consisting of halo, C1-
10alkyl,
C1-10 substituted alkyl, C3-7cycloalkyl, C2-10alkenyl, C2-10alkynyl, -CN, -NO
2,
-ORa, -NRaRb, -CORa, -CO 2Ra, -CONRaRb, -NRaCORb, -NRaCO 2Rb,
-NRaCONRaRb, -S(O)mRa, -NRaS(O)mRb, -SO 2NRaRb, a 4- to 7-membered heterocyclo

group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said
heterocyclo
groups, said aryl and heteroaryl groups are optionally substituted with from
one to four
substituents independently selected from halo, oxo, C1-4 alkyl, C1-4
haloalkyl, C3-7
cycloalkyl, -CN, -NO 2, -ORa, -NRaRb, -CORa,
-CO 2Ra, -CONRaRb, -NRaCORb, -NRaCO 2Rb, -NRaCONRaRb, -S(O)mRa,
-NRaSO 2Rb, and -SO 2NRaRb and wherein the subscript m is an integer of from 0
to 2, or
optionally Ra and Rb are combined to form a 4-, 5- or 6-membered ring;
le is a member independently selected from the group consisting of hydrogen,
C1-4alkyl, and C1-4haloalkyl;
and each Ra and Rb is independently selected from the group consisting of
hydrogen, C1-10
alkyl, C1-10haloalkyl, C3-10cycloalkyl, heterocyclyl, C2-10alkenyl,
C2-10alkynyl, aryl, 5- to 6-membered heteroaryl and arylC1-4alkyl; and wherein
the
aliphatic portions of each of said Ra and Rb is optionally substituted with
from one to
three members selected from the group consisting of halo, -OR11, -OCORn,
-OC(O)N(Rn)2, -SRn, -S(O)Rn, -S(O)2Rn, -S(O)2N(Rn)2, -NRnS(O)2Rn,
-C(O)N(Rn)2, -C(O)Rn, -NRnC(O)Rn, -NRnC(O)N(Rn)2, -CO 2Rn, -NRnCO 2Rn,
-CN, -NO 2, -N(Rn)2 and -NRnS(O)2N(Rn)2, wherein each Rn is independently
hydrogen
or an unsubstituted C1-6 alkyl;
and wherein the aryl and heteroaryl portions are optionally substituted with
from one to three
168

members selected from
halogen, -OR m, -OC(O)N(R m)2, -SR m, -S(O)R m, -S(O)2R m, -S(O)2N(R m)2,
-NR mS(O)2R m, -C(O)N(R m)2, -C(O)R m, -NR mC(O)R m, -NR mC(O)N(R m)2,
-CO2R m, -NR m CO2R m, -CN, -NO2, -N(R m)2 and -NR mS(O)2N(R m)2, wherein each
R m is
independently hydrogen or an unsubstituted C1-6 alkyl;
or a pharmaceutically acceptable salt or ester thereof; and
wherein the molecular weight of said compound is less than 1200.
10. The method of claim 9, wherein said compound of Formula I is selected
from the
group consisting of the compound of example 52, 76, 77, 95, 148, 162, 170,
171, 182,
184, 185, and 195, or a pharmaceutically acceptable salt thereof.
11. The method of claim 10, wherein said compound of Formula (I) is
Image
or a pharmaceutically acceptable salt thereof.
12. The method of any one of claims 9-11, further comprising concurrently
or
sequentially administering a DPP-IV inhibitor to the patient.
13. The method of claim 12, wherein said DPP-IV inhibitor is selected from
the group
consisting of sitagliptin, vildagliptin, denagliptin, saxagliptin,
linagliptin, alogliptin,
R1438, NVP DPP728, PSN9301, P32/98, NN-7201, ALS2-0426, gemigliptin,
anagliptin, teneligliptin, trelagliptin, dutogliptin, and omarigliptin.
14. The method of claim 12 or claim 13, wherein said DPP-IV inhibitor is
selected from
the group consisting of sitagliptin, vildagliptin, saxagliptin, linagliptin,
gemigliptin,
anagliptin, teneligliptin, trelagliptin, omarigliptin, and alogliptin.

169

15. The method of any one of claims 9-14, further comprising concurrently
or
sequentially administering metformin to the patient.
16. A method of treating inflammatory bowel disease in a patient in need
thereof, the
method comprising administering to the patient a therapeutically effective
amount of
a compound of Formula (I),
Image
wherein,
D is selected from the group consisting of O, S, and NR8,
X, Y, and Z are independently selected from the group consisting of O, N, NR8,
S, and CR3
and at least one of X, Y, and Z is O, N, NR8, or S;
J, K, T, and U are each independently selected from the group consisting of C,
CH, and N;
the subscript p is an integer of from 0 to 4;
the subscript q is an integer of from 0 to 4;
R1 is a member selected from the group consisting of H, C1-10alkyl, C1-
10substituted alkyl, C3-
7cycloalkyl, C2-10alkenyl, C2-10alkynyl, -X1-CORa,-X1-CO2Ra,
-X1-CONRaRb, -SO2Ra, a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-

membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo
group,
aryl group and heteroaryl group is optionally substituted with from 1 to 4
substituents
independently selected from halo, C1-10alkyl,
C1-10substituted alkyl, C3-7cycloalkyl, C2-10 alkenyl, C2-10alkynyl, aryl,
heteroaryl, -CN, -NRaCORb, -NRaCONRaRb, -NO2, -ORa, -NRaRb, -CORa,
-CO2Ra, -CONRaRb, -S(O)mRa, -NRaS(O)2Rb, and -SO2NRaRb, or optionally Ra and
Rb
are combined to form a 4-, 5- or 6-membered ring, and X1 is selected from the
group
consisting of a bond, C2-6alkene, C2-6alkyne, -C(O)-, and
-C(O)-(CH2)1-4-, wherein the aliphatic portions of X1 are optionally
substituted with one
to three members selected from halogen, C1-4alkyl, C1-4substituted alkyl and
C1-
4haloalkyl;
170

each R2 is a member independently selected from the group consisting of
halogen,
C1-5 alkyl, C1-5substituted alkyl, C3-7cycloalkyl, -CORa, -CO2Ra, -CONRaRb, -
ORa,
-NRaRb, -NRaCORb, -SORaRb, -SO2Ra and -SO2NRaRb, and wherein when the
subscript
q is 2 and R2 is alkyl or substituted alkyl, the two R2 members can optionally
cyclize to
form a ring;
R3 is a member selected from the group consisting of hydrogen, halogen, C1-
4alkyl, and C1-
4haloalkyl;
each R7 is independently selected from the group consisting of halo, C1-
10alkyl,
C1-10 substituted alkyl, C3-7cycloalkyl, C2-10alkenyl, C2-10alkynyl, -CN, -
NO2,
-ORa, -NRaRb, -CORa, -CO2Ra, -CONRaRb, -NRaCORb, -NRaCO2Rb,
-NRaCONRaRb, -S(O)mRa, -NRaS(O)mRb, -SO2NRaRb, a 4- to 7-membered heterocyclo
group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said
heterocyclo
groups, said aryl and heteroaryl groups are optionally substituted with from
one to four
substituents independently selected from halo, oxo, C1-4 alkyl, C1-4
haloalkyl, C3-7
cycloalkyl, -CN, -NO2, -ORa, -NRaRb, -CORa,
-CO2Ra, -CONRaRb, -NRaCORb, -NRaCO2Rb, -NRaCONRaRb, -S(O)mRa,
-NRaSO2Rb, and -SO2NRaRb and wherein the subscript m is an integer of from 0
to 2, or
optionally Ra and Rb are combined to form a 4-, 5- or 6-membered ring;
R8 is a member independently selected from the group consisting of hydrogen,
C1-4alkyl, and C1-4haloalkyl;
and each Ra and Rb is independently selected from the group consisting of
hydrogen, C1-10
alkyl, C1-10haloalkyl, C3-10cycloalkyl, heterocyclyl, C2-10alkenyl,
C2-10alkynyl, aryl, 5- to 6-membered heteroaryl and arylC1-4alkyl; and wherein
the
aliphatic portions of each of said Ra and Rb is optionally substituted with
from one to
three members selected from the group consisting of halo, -ORn, -OCORn,
-OC(O)N(Rn)2, -SRn, -S(O)Rn, -S(O)2Rn, -S(O)2N(Rn)2, -NRnS(O)2Rn,
-C(O)N(Rn)2, -C(O)Rn, -NRnC(O)Rn, -NRnC(O)N(Rn)2, -CO2Rn, -NRnCO2Rn,
-CN, -NO2, -N(Rn)2 and -NRnS(O)2N(Rn)2, wherein each Rn is independently
hydrogen
or an unsubstituted C1-6 alkyl;
and wherein the aryl and heteroaryl portions are optionally substituted with
from one to three
members selected from
halogen, -ORm, -OC(O)N(Rm)2, -SRm, -S(O)Rm, -S(O)2Rm, -S(O)2N(Rm)2,
171

-NRmS(O)2Rm, -C(O)N(Rm)2, -C(O)Rm, -NRmC(O)Rm, -NRmC(O)N(Rm)2,
-CO2Rm, -NRmCO2Rm, -CN, -NO2, -N(Rm)2 and -NRmS(O)2N(Rm)2, wherein each Rm is
independently hydrogen or an unsubstituted C1-6 alkyl;
or a pharmaceutically acceptable salt or ester thereof; and
wherein the molecular weight of said compound is less than 1200.
17. The method of claim 16, wherein said compound of Formula I is selected
from the
group consisting of the compound of example 52, 76, 77, 95, 148, 162, 170,
171, 182,
184, 185, and 195, or a pharmaceutically acceptable salt thereof.
18. The method of claim 17, wherein said compound of Formula (I) is
Image
or a pharmaceutically acceptable salt thereof.
19. The method of any one of claims 16-18, further comprising concurrently
or
sequentially administering a DPP-IV inhibitor to the patient.
20. The method of claim 19, wherein said DPP-IV inhibitor is selected from
the group
consisting of sitagliptin, vildagliptin, denagliptin, saxagliptin,
linagliptin, alogliptin,
R1438, NVP DPP728, PSN9301, P32/98, NN-7201, ALS2-0426, gemigliptin,
anagliptin, teneligliptin, trelagliptin, dutogliptin, and omarigliptin.
21. The method of claim 19 or claim 20, wherein said DPP-IV inhibitor is
selected from
the group consisting of sitagliptin, vildagliptin, saxagliptin, linagliptin,
gemigliptin,
anagliptin, teneligliptin, trelagliptin, omarigliptin, and alogliptin.
22. The method of any one of claims 16-21, further comprising concurrently
or
sequentially administering metformin to the patient.
172

23. The
method of any one of claims 16-22, wherein the inflammatory bowel disease is
Crohn's disease or ulcerative colitis.
173

Description

CA 03032432 2019-01-29
WO 2018/026890 PCT/US2017/045050
OXYMETHYLENE ARYL COMPOUNDS FOR TREATING INFLAMMATORY
GASTROINTESTINAL DISEASES OR GASTROINTESTINAL CONDITIONS
FIELD
[0001] The present disclosure relates to methods of treating an inflammatory
gastrointestinal
disease or a gastrointestinal condition involving malabsorption of nutrients
and/or fluids in a
patient in need thereof.
SUMMARY
[0002] In one aspect, provided herein are methods of treating an inflammatory
gastrointestinal
disease or a gastrointestinal condition in a patient in need thereof. In one
embodiment, the
inflammatory gastrointestinal disease or the gastrointestinal condition
involves malabsorption
of nutrients and/or fluids. In another embodiment, the method comprising
administering to the
patient a therapeutically effective amount of a compound of Formula (I),
X¨Y
R1 U (R7)p
(R2 )q
(I)
wherein,
D is selected from the group consisting of 0, S, and Nle,
X, Y, and Z are independently selected from the group consisting of 0, N,
NIR8, S, and CR3
and at least one of X, Y, and Z is 0, N, Nle, or S;
J, K, T, and U are each independently selected from the group consisting of C,
CH, and N;
the subscript p is an integer of from 0 to 4;
the subscript q is an integer of from 0 to 4;
R' is a member selected from the group consisting of H, Ci_ioalkyl,
Ci_iosubstituted alkyl, C3-
7cyc1oa1ky1, C2.10alkenyl, C2.10alkynyl, -Xl-CORa, -Xl-CO2Ra,
-Xi_c 0NRa
K SO2Ra, a 4- to 7-membered heterocyclo group, aryl and a 5-
to 10-
membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo
group,
aryl group and heteroaryl group is optionally substituted with from 1 to 4
substituents
independently selected from halo, Ci_ioalkyl,
Ci_iosubstituted alkyl, C3_7cycloalkyl, C2-10 alkenyl, C2.10alkynyl, aryl,
1

CA 03032432 2019-01-29
WO 2018/026890 PCT/US2017/045050
heteroaryl, -CN, -NleCORb, -NRaCONIeltb, -NO2, -01e, -NRaltb, -COW,
-0O21e, -CONIeltb, -S(0)le, -NleS(0)2Rb, and ¨SO2NRaltb, or optionally le and
Rb
are combined to form a 4-, 5- or 6-membered ring, and X' is selected from the
group
consisting of a bond, C2.6alkene, C2_6alkyne, -C(0)-, and
-C(0)-(CH2)1.4-, wherein the aliphatic portions of Xl are optionally
substituted with one
to three members selected from halogen, Ci.4alkyl, C1.4substituted alkyl and
Ci-
4haloalkyl;
each R2 is a member independently selected from the group consisting of
halogen,
C1-5 alkyl, C1-5substituted alkyl, C3-7cycloalkyl, -CORa, -0O21e, -CONIeltb, -
01e,
-NRaltb, -NleCORb, -SOW Rb, -S021e and -SO2NRaltb, and wherein when the
subscript
q is 2 and R2 is alkyl or substituted alkyl, the two R2 members can optionally
cyclize to
form a ring;
R3 is a member selected from the group consisting of hydrogen, halogen,
Ci.4alkyl, and C1.
4ha1oa1ky1;
each R7 is independently selected from the group consisting of halo,
Ci_loalkyl,
C1.10 substituted alkyl, C3_7cycloalkyl, C2.10alkenyl, C2.10alkynyl, -CN, -
NO2,
-01e, -NRaltb, -COW, -0O21e, -CONIeltb, -NleCORb, -NRaCO2Rb,
-NleCONIeltb, -S(0)le, -NleS(0)Rb, -SO2NRaltb, a 4- to 7-membered heterocyclo
group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said
heterocyclo
groups, said aryl and heteroaryl groups are optionally substituted with from
one to four
sub stituents independently selected from halo, oxo, C1-4 alkyl, C1-4
haloalkyl, C3-7
cycloalkyl, -CN, -NO2, -01e, -NRaltb, -COW,
-0O21e, -CONIeltb, -NRaCORb, 4leCO2Rb, -NleCONIeltb,
-NleS02Rb, and -SO2NRaltb and wherein the subscript m is an integer of from 0
to 2, or
optionally le and Rb are combined to form a 4-, 5- or 6-membered ring;
R8 is a member independently selected from the group consisting of hydrogen,
Ci.4alkyl, and Ci.4haloalkyl;
and each le and Rb is independently selected from the group consisting of
hydrogen, C1-10
alkyl, Ci_lohaloalkyl, C3.10cycloalkyl, heterocyclyl, C2.10alkenyl,
C2.10alkynyl, aryl, 5- to 6-membered heteroaryl and ary1C1.4alkyl; and wherein
the
aliphatic portions of each of said le and Rb is optionally substituted with
from one to
three members selected from the group consisting of halo, -Or, -000R11,
2

CA 03032432 2019-01-29
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-0C(0)N(102, -S(0)1e, -S(0)21e, -S(0)2N(102, -NIVS(0)21e,
-C(0)N(102, -C(0)1e, -NIVC(0)1e, -NRI1C(0)N(R11)2, -0O21e, -NIVCO2R11,
-CN, -NO2, -N(102 and -NleS(0)2N(102, wherein each le is independently
hydrogen
or an unsubstituted C1.6 alkyl;
and wherein the aryl and heteroaryl portions are optionally substituted with
from one to three
members selected from
halogen, -OR', -0C(0)N(Rm)2, -S(0)Rin, -S(0)2Rin, -S(0)2N(Rm)2,
-NRInS(0)2Rm, -C(0)N(Rm)2, -C(0)Rin, -NItmC(0)Rin, -NItmC(0)N(Rin)2,
-CO2Rin, -NRITO2Rm, -CN, -NO2, -N(Rm)2 and -NR'S(0)2N(Rm)2, wherein each Itm
is
independently hydrogen or an unsubstituted C1.6 alkyl;
or a pharmaceutically acceptable salt or ester thereof; and
wherein the molecular weight of said compound is less than 1200.
[0003] In some embodiments, the compound of Formula I is selected from the
group
consisting of the compound of example 52, 76, 77, 95, 148, 162, 170, 171, 182,
184, 185, and
195, or a pharmaceutically acceptable salt thereof. In some embodiments, the
compound of
N N
r(): 0
m
K1
I /IN
Formula (I) is NN
or a pharmaceutically acceptable salt thereof. In some embodiments, the method
further
comprises concurrently or sequentially administering a DPP-IV inhibitor to the
patient. In some
embodiments, the DPP-IV inhibitor is selected from the group consisting of
sitagliptin,
vildagliptin, denagliptin, saxagliptin, linagliptin, alogliptin, R1438, NVP
DPP728, PSN9301,
P32/98, NN-7201, ALS2-0426, gemigliptin, anagliptin, teneligliptin,
trelagliptin, dutogliptin,
and omarigliptin. In some embodiments, the DPP-IV inhibitor is selected from
the group
consisting of sitagliptin, vildagliptin, saxagliptin, linagliptin,
gemigliptin, anagliptin,
teneligliptin, trelagliptin, omarigliptin, and alogliptin. In some
embodiments, the inflammatory
gastrointestinal disease or the gastrointestinal condition involving
malabsorption of nutrients
and/or fluids is selected from the group consisting of short bowel syndrome
(SBS),
inflammatory bowel disease, Crohn's disease, ulcerative colitis, volvulus, and
necrotizing
enterocolitis. In some embodiments, the method further comprises concurrently
or sequentially
administering metformin to the patient.
3

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[0004] In another aspect, provided herein are methods of treating short bowel
syndrome in a
patient in need thereof, the method comprising administering to the patient a
therapeutically
effective amount of a compound of Formula (I),
NTQ
R1 U (R7)p
(R2 )q
(I)
wherein,
D is selected from the group consisting of 0, S, and Nle,
X, Y, and Z are independently selected from the group consisting of 0, N,
NIR8, S, and CR3
and at least one of X, Y, and Z is 0, N, Nle, or S;
J, K, T, and U are each independently selected from the group consisting of C,
CH, and N;
the subscript p is an integer of from 0 to 4;
the subscript q is an integer of from 0 to 4;
R' is a member selected from the group consisting of H, Ci_ioalkyl,
Ci_iosubstituted alkyl, C3-
7cyc1oa1ky1, C2.10alkenyl, C2.10alkynyl, XlCORa,-Xl-0O21e,
- XlCONIRaRb,-S021e, a 4- to 7-membered heterocyclo group, aryl and a 5- to
10-
membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo
group,
aryl group and heteroaryl group is optionally substituted with from 1 to 4
substituents
independently selected from halo, Ci_ioalkyl,
Ci_iosubstituted alkyl, C3_7cycloalkyl, C2-10 alkenyl, C2.10alkynyl, aryl,
heteroaryl, -CN, -NleCORb, -NRaCONIeltb, -NO2, -01e, -NRaltb, -COW,
-0O21e, -CONIeltb, -S(0)le, -NleS(0)2Rb, and ¨SO2NRaltb, or optionally le and
Rb
are combined to form a 4-, 5- or 6-membered ring, and Xl is selected from the
group
consisting of a bond, C2_6alkene, C2_6alkyne, -C(0)-, and -C(0)-(CH2)1.4-,
wherein the
aliphatic portions of Xl are optionally substituted with one to three members
selected
from halogen, Ci_4alkyl, C1_4substituted alkyl and Ci_4haloalkyl;
each R2 is a member independently selected from the group consisting of
halogen,
C1-5 alkyl, C1-5substituted alkyl, C 3_7 cycloalkyl, -COW, -0O21e, -CONIeltb, -
01e,
-NRaltb, -NleCORb, -SOW Rb, -S021e and -SO2NRaltb, and wherein when the
subscript
q is 2 and R2 is alkyl or substituted alkyl, the two R2 members can optionally
cyclize to
4

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form a ring;
R3 is a member selected from the group consisting of hydrogen, halogen,
Ci.4alkyl, and C1.
4ha1oa1ky1;
each R7 is independently selected from the group consisting of halo,
Ci_loalkyl,
Ci_io substituted alkyl, C3,7cycloalkyl, C2-ioalkenyl, C2.10alkynyl, -CN, -
NO2,
-0Ra, -NRaRb, -CORa, -CO2Ra, -CONRaRb, -NRaCORb, -NRaCO2Rb,
-NRaCONRaRb, -S(0)Ra, -NRaS(0).Rb, -SO2NRaRb, a 4- to 7-membered heterocyclo
group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said
heterocyclo
groups, said aryl and heteroaryl groups are optionally substituted with from
one to four
sub stituents independently selected from halo, oxo, C1-4 alkyl, C1-4
haloalkyl, C3-7
cycloalkyl, -CN, -NO2, -0Ra, -NRaRb, -CORa,
-0O2Ra, -CONRaRb, -NRaCORb, 4RaCO2Rb, -NRaCONRaRb, -S(0)Ra,
-NRaSO2Rb, and -SO2NRaRb and wherein the subscript m is an integer of from 0
to 2, or
optionally Ra and Rb are combined to form a 4-, 5- or 6-membered ring;
R8 is a member independently selected from the group consisting of hydrogen,
Ci.4alkyl, and Ci.4haloalkyl;
and each Ra and Rb is independently selected from the group consisting of
hydrogen, Ci-io
alkyl, Ci_lohaloalkyl, C3.10cycloalkyl, heterocyclyl, C2_10alkenyl,
C2.10alkynyl, aryl, 5- to 6-membered heteroaryl and ary1C1.4alkyl; and wherein
the
aliphatic portions of each of said Ra and Rb is optionally substituted with
from one to
three members selected from the group consisting of halo, -Or, -000le,
-0C(0)N(102, -S(0)1e, -S(0)21e, -S(0)2N(102, -NIVS(0)21e,
-C(0)N(102, -C(0)1e, -NIVC(0)1e, -NleC(0)N(R11)2, -0O21e, -NIVCO2r,
-CN, -NO2, -N(102 and -NleS(0)2N(102, wherein each le is independently
hydrogen
or an unsubstituted C1.6 alkyl;
and wherein the aryl and heteroaryl portions are optionally substituted with
from one to three
members selected from
halogen, -OR', -0C(0)N(Rm)2, -S(0)Itin, -S(0)21tm, -S(0)2N(Rm)2,
-NRInS(0)2Rm, -C(0)N(Rm)2, -C(0)Itin, -NItmC(0)Rin, -NItmC(0)N(Rin)2,
-0O21tin, -NRInCO21tm, -CN, -NO2, -N(Itm)2 and -NRInS(0)2N(Rm)2, wherein each
RI' is
independently hydrogen or an unsubstituted C1.6 alkyl;

CA 03032432 2019-01-29
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or a pharmaceutically acceptable salt or ester thereof; and
wherein the molecular weight of said compound is less than 1200.
[0005] In some embodiments, the compound of Formula I is selected from the
group
consisting of the compound of example 52, 76, 77, 95, 148, 162, 170, 171, 182,
184, 185, and
195, or a pharmaceutically acceptable salt thereof. In some embodiments, the
compound of
N N 0
r(7
N N
Formula (I) is Nj
or a pharmaceutically acceptable salt thereof. In some embodiments, the method
further
comprises concurrently or sequentially administering a DPP-IV inhibitor to the
patient. In some
embodiments, the DPP-IV inhibitor is selected from the group consisting of
sitagliptin,
vildagliptin, denagliptin, saxagliptin, linagliptin, alogliptin, R1438, NVP
DPP728, PSN9301,
P32/98, NN-7201, ALS2-0426, gemigliptin, anagliptin, teneligliptin,
trelagliptin, dutogliptin,
and omarigliptin. In some embodiments, the DPP-IV inhibitor is selected from
the group
consisting of sitagliptin, vildagliptin, saxagliptin, linagliptin,
gemigliptin, anagliptin,
teneligliptin, trelagliptin, omarigliptin, and alogliptin. In some
embodiments, the method further
comprises concurrently or sequentially administering metformin to the patient.
[0006] In another aspect, provided herein are methods of treating inflammatory
bowel disease
in a patient in need thereof, the method comprising administering to the
patient a therapeutically
effective amount of a compound of Formula (I),
fZUZD
QK
T
R1 NA U (R7)p
(R2 )ci
(I)
wherein,
D is selected from the group consisting of 0, S, and NR8,
X, Y, and Z are independently selected from the group consisting of 0, N, NR8,
S, and CR3
and at least one of X, Y, and Z is 0, N, NR8, or S;
J, K, T, and U are each independently selected from the group consisting of C,
CH, and N;
6

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the subscript p is an integer of from 0 to 4;
the subscript q is an integer of from 0 to 4;
R' is a member selected from the group consisting of H, Ci_ioalkyl,
Ci_iosubstituted alkyl, C3_
7cyc1oa1ky1, C2.10alkenyl, C2.10alkynyl, -Xl-CORa, -Xl-CO2Ra,
-Xl-CONRaRb, -SO2Ra, a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-

membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo
group,
aryl group and heteroaryl group is optionally substituted with from 1 to 4
substituents
independently selected from halo, Ci_ioalkyl,
Ci_iosubstituted alkyl, C3_7cycloalkyl, C2-10 alkenyl, C2.10alkynyl, aryl,
heteroaryl, -CN, -NRaCORb, -NRaCONRaRb, -NO2, -0Ra, -NRaRb, -CORa,
-CO2Ra, -CONRaRb, -S(0)Ra, -NRaS(0)2Rb, and ¨SO2NRaRb, or optionally Ra and Rb

are combined to form a 4-, 5- or 6-membered ring, and Xl is selected from the
group
consisting of a bond, C2.6alkene, C2_6alkyne, -C(0)-, and
-C(0)-(CH2)1.4-, wherein the aliphatic portions of Xl are optionally
substituted with one
to three members selected from halogen, Ci.4alkyl, C1.4substituted alkyl and
Ci-
4haloalkyl;
each R2 is a member independently selected from the group consisting of
halogen,
C1-5 alkyl, C1-5substituted alkyl, C3-7cycloalkyl, -CORa, -CO2Ra, -CONRaRb, -
0Ra,
-NRaRb, -NRaCORb, -SORaRb, -SO2Ra and -SO2NRaRb, and wherein when the
subscript
q is 2 and R2 is alkyl or substituted alkyl, the two R2 members can optionally
cyclize to
form a ring;
R3 is a member selected from the group consisting of hydrogen, halogen,
Ci.4alkyl, and C1.
4ha1oa1ky1;
each R7 is independently selected from the group consisting of halo,
Ci_loalkyl,
C1.10 substituted alkyl, C3,7cycloalkyl, C2.10alkenyl, C2.10alkynyl, -CN, -
NO2,
-0Ra, -NRaRb, -CORa, -CO2Ra, -CONRaRb, -NRaCORb, -NRaCO2Rb,
-NRaCONRaRb, -S(0)Ra, -NRaS(0)Rb, -SO2NRaRb, a 4- to 7-membered heterocyclo
group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said
heterocyclo
groups, said aryl and heteroaryl groups are optionally substituted with from
one to four
sub stituents independently selected from halo, oxo, C1-4 alkyl, C1-4
haloalkyl, C3-7
cycloalkyl, -CN, -NO2, -0Ra, -NRaRb, -CORa,
-0O2Ra, -CONRaRb, -NRaCORb, 4RaCO2Rb, -NRaCONRaRb, -S(0)Ra,
7

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-NleS02Rb, and -SO2Nlele and wherein the subscript m is an integer of from 0
to 2, or
optionally le and Rb are combined to form a 4-, 5- or 6-membered ring;
R8 is a member independently selected from the group consisting of hydrogen,
Ci_4alkyl, and Ci4haloalkyl;
and each le and Rb is independently selected from the group consisting of
hydrogen, C1-10
alkyl, Cmohaloalkyl, C3.10cycloalkyl, heterocyclyl, C2.10alkenyl,
C2.10alkynyl, aryl, 5- to 6-membered heteroaryl and ary1C1.4alkyl; and wherein
the
aliphatic portions of each of said le and Rb is optionally substituted with
from one to
three members selected from the group consisting of halo, -Or, -000le,
-0C(0)N(102, -SR, -S(0)1e, -S(0)21e, -S(0)2N(102, -NleS(0)21e,
-C(0)N(102, -C(0)1e, -NleC(0)Rn, -NleC(0)N(R11)2, -0O21e, -NleCO2R11,
-CN, -NO2, -N(le)2 and -NleS(0)2N(102, wherein each le is independently
hydrogen
or an unsubstituted C1-6 alkyl;
and wherein the aryl and heteroaryl portions are optionally substituted with
from one to three
members selected from
halogen, -OR', -0C(0)N(le)2, -S(0)Rm, -S(0)2Ie', -S(0)2N(le)2,
-Nle'S(0)2Rm, -C(0)N(le)2, -C(0)Rm, -Nle'C(0)Rm, -Nle'C(0)N(Rm)2,
-0O21e', -Nle'CO2Rm, -CN, -NO2, -N(le)2 and -Nle'S(0)2N(Rm)2, wherein each le'
is
independently hydrogen or an unsubstituted C1.6 alkyl;
or a pharmaceutically acceptable salt or ester thereof; and
wherein the molecular weight of said compound is less than 1200.
[0007] In some embodiments, the compound of Formula I is selected from the
group
consisting of the compound of example 52, 76, 77, 95, 148, 162, 170, 171, 182,
184, 185, and
195, or a pharmaceutically acceptable salt thereof. In some embodiments, the
compound of
(NN) 0 =
(NN m,
K1
Formula (I) is Nj
or a pharmaceutically acceptable salt thereof. In some embodiments, the method
further
comprises concurrently or sequentially administering a DPP-IV inhibitor to the
patient. In some
embodiments, the DPP-IV inhibitor is selected from the group consisting of
sitagliptin,
vildagliptin, denagliptin, saxagliptin, linagliptin, alogliptin, R1438, NVP
DPP728, PSN9301,
8

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P32/98, NN-7201, ALS2-0426, gemigliptin, anagliptin, teneligliptin,
trelagliptin, dutogliptin,
and omarigliptin. In some embodiments, the DPP-IV inhibitor is selected from
the group
consisting of sitagliptin, vildagliptin, saxagliptin, linagliptin,
gemigliptin, anagliptin,
teneligliptin, trelagliptin, omarigliptin, and alogliptin. In some
embodiments, the method further
comprises concurrently or sequentially administering metformin to the patient.
In some
embodiments, the inflammatory bowel disease is Crohn's disease or ulcerative
colitis.
DETAILED DESCRIPTION
[0008] Various embodiments are described hereinafter. It should be noted that
the specific
embodiments are not intended as an exhaustive description or as a limitation
to the broader
aspects discussed herein. One aspect described in conjunction with a
particular embodiment is
not necessarily limited to that embodiment and can be practiced with any other
embodiment(s).
[0009] Unless otherwise stated, the following terms used in the specification
and claims have
the meanings given below:
[0010] As used herein, "about" will be understood by persons of ordinary skill
in the art and
will vary to some extent depending upon the context in which it is used. If
there are uses of the
term which are not clear to persons of ordinary skill in the art, given the
context in which it is
used, "about" will mean up to plus or minus 10% of the particular term.
[0011] The use of the terms "a" and "an" and "the" and similar referents in
the context of
describing the elements (especially in the context of the following claims)
are to be construed to
cover both the singular and the plural, unless otherwise indicated herein or
clearly contradicted
by context. Recitation of ranges of values herein are merely intended to serve
as a shorthand
method of referring individually to each separate value falling within the
range, unless otherwise
indicated herein, and each separate value is incorporated into the
specification as if it were
individually recited herein. All methods described herein can be performed in
any suitable order
unless otherwise indicated herein or otherwise clearly contradicted by
context. The use of any
and all examples, or exemplary language (e.g., "such as") provided herein, is
intended merely to
better illuminate the embodiments and does not pose a limitation on the scope
of the claims
unless otherwise stated. No language in the specification should be construed
as indicating any
non-claimed element as essential.
9

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[0012] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups
having from 1 to
carbon atoms and, in some embodiments, from 1 to 6 carbon atoms. "Calkyl"
refers to
alkyl groups having from u to v carbon atoms. This term includes, by way of
example, linear
and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-
propyl
(CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl
((CH3)2CHCH27),
sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-),
and
neopentyl ((CH3)3CCH2-).
[0013] "Substituted alkyl" refers to an alkyl group having from 1 to 5 and, in
some
embodiments, 1 to 3 or 1 to 2 substituents selected from the group consisting
of alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy,
acyl, acylamino,
acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl,
aminocarbonylamino,
aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy,
aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted
aryloxy, arylthio,
substituted arylthio, azido, carboxyl, carboxyl ester, (carboxyl ester)amino,
(carboxyl ester)oxy,
cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted
cycloalkyloxy,
cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino,
halo, hydroxy,
hydroxyamino, alkoxyamino, hydrazino, substituted hydrazino, heteroaryl,
substituted
heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio,
substituted heteroarylthio,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy,
heterocyclylthio, substituted heterocyclylthio, nitro, spirocycloalkyl, 503H,
substituted sulfonyl,
sulfonyloxy, thioacyl, thiocyanate, thiol, alkylthio, and substituted
alkylthio, wherein said
substituents are as defined herein.
[0014] "Alkylidene" or "alkylene" refers to divalent saturated aliphatic
hydrocarbyl groups
having from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6 carbon
atoms.
"(C)alkylene" refers to alkylene groups having from u to v carbon atoms. The
alkylidene and
alkylene groups include branched and straight chain hydrocarbyl groups. For
example "(C1_
6)alkylene" is meant to include methylene, ethylene, propylene,
2-methypropylene, pentylene, and the like.
[0015] "Substituted alkylidene" or "substituted alkylene" refers to an
alkylidene group having
from 1 to 5 and, in some embodiments, 1 to 3 or 1 to 2 substituents selected
from the group
consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino,
substituted amino,

CA 03032432 2019-01-29
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aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino,
amidino, aryl,
substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted
arylthio, azido, carboxyl,
carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl,
substituted
cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio,
substituted cycloalkylthio,
guanidino, substituted guanidino, halo, hydroxy, hydroxyamino, alkoxyamino,
hydrazino,
substituted hydrazino, heteroaryl, substituted heteroaryl, heteroaryloxy,
substituted
heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic,
substituted heterocyclic,
heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted
heterocyclylthio,
nitro, oxo, thione, spirocycloalkyl, SO3H, substituted sulfonyl, sulfonyloxy,
thioacyl,
thiocyanate, thiol, alkylthio, and substituted alkylthio, wherein said
substituents are as defined
herein.
[0016] "Alkenyl" refers to a linear or branched hydrocarbyl group having from
2 to 10 carbon
atoms and in some embodiments from 2 to 6 carbon atoms or 2 to 4 carbon atoms
and having at
least 1 site of vinyl unsaturation ( C=C). For example, (C,i-v)alkenyl refers
to alkenyl groups
having from u to v carbon atoms and is meant to include for example, ethenyl,
propenyl, 1,3-
butadienyl, and the like.
[0017] "Substituted alkenyl" refers to alkenyl groups having from 1 to 3
substituents and, in
some embodiments, 1 to 2 sub stituents, selected from the group consisting of
alkoxy, substituted
alkoxy, acyl, acylamino, acyloxy, alkyl, substituted alkyl, alkynyl,
substituted alkynyl, amino,
substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,
aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy,
aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted
aryloxy, arylthio,
substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino,
(carboxyl ester)oxy, cyano,
cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy,
cycloalkylthio,
substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy,
heteroaryl,
substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy,
heteroarylthio, substituted
heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,
substituted
heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, 503H,
substituted
sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio,
wherein said
substituents are defined as herein and with the proviso that any hydroxy or
thiol substitution is
not attached to an acetylenic carbon atom.
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[0018] "Alkynyl" refers to a linear monovalent hydrocarbon radical or a
branched monovalent
hydrocarbon radical containing at least one triple bond. The term "alkynyl" is
also meant to
include those hydrocarbyl groups having one triple bond and one double bond.
For example,
(C2-C6)alkynyl is meant to include ethynyl, propynyl, and the like.
[0019] "Substituted alkynyl" refers to alkynyl groups having from 1 to 3
substituents and, in
some embodiments, from 1 to 2 sub stituents, selected from the group
consisting of alkoxy,
substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino,
aminocarbonyl,
aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy,
aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,
substituted aryl, aryloxy,
substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester,
(carboxyl
ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl,
cycloalkyloxy,
substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio,
cycloalkenyl, substituted
cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio,
substituted
cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl,
substituted
heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio,
substituted heteroarylthio,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy,
heterocyclylthio, substituted heterocyclylthio, nitro, 503H, substituted
sulfonyl, sulfonyloxy,
thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said
substituents are defined herein
and with the proviso that any hydroxy or thiol substitution is not attached to
an acetylenic
carbon atom.
[0020] "Alkoxy" refers to the group -0-alkyl wherein alkyl is defined herein.
Alkoxy
includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
t-butoxy,
sec-butoxy, and n-pentoxy.
[0021] "Substituted alkoxy" refers to the group -0-(substituted alkyl) wherein
substituted
alkyl is as defined herein.
[0022] "Acyl" refers to the groups H-C(0)-, alkyl-C(0)-, substituted alkyl-
C(0)-,
alkenyl-C(0)-, substituted alkenyl-C(0)-, alkynyl-C(0)-, substituted alkynyl-
C(0)-,
cycloalkyl-C(0)-, substituted cycloalkyl-C(0)-, aryl-C(0)-, substituted aryl-
C(0)-, substituted
hydrazino-C(0)-, heteroaryl-C(0)-, substituted heteroaryl-C(0)-, heterocyclic-
C(0)-, and
substituted heterocyclic-C(0)-, wherein alkyl, substituted alkyl, alkenyl,
substituted alkenyl,
alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,
substituted aryl, substituted
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hydrazino, heteroaryl, substituted heteroaryl, heterocyclic and substituted
heterocyclic are as
defined herein. Acyl includes the "acetyl" group CH3C(0)-.
[0023] "Acylamino" refers to the groups -NR20C(0)H, -NR20C(0)alkyl,
_¨
INK20 C(0)substituted alkyl, -NR20C(0)cycloalkyl, -NR20C(0)substituted
cycloalkyl, -NR20C(0)alkenyl, -NR20C(0)substituted alkenyl, -NR20C(0)alkynyl,
_¨
INK20 C(0)substituted alkynyl, -NR20C(0)aryl, -NR20C(0)substituted aryl,
_¨
INK20 C(0)heteroaryl, -NR20C(0)substituted heteroaryl, -NR20C(0)heterocyclic,
and -NR20C(0)substituted heterocyclic wherein R2 is hydrogen or alkyl and
wherein alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl,
substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, heterocyclic and
substituted heterocyclic are as defined herein.
[0024] "Acyloxy" refers to the groups H-C(0)0-, alkyl-C(0)O-, substituted
alkyl-C(0)O-,
alkenyl-C(0)O-, substituted alkenyl-C(0)O-, alkynyl-C(0)O-, substituted
alkynyl-C(0)O-,
aryl-C(0)O-, substituted aryl-C(0)O-, cycloalkyl-C(0)O-, substituted
cycloalkyl-C(0)O-,
heteroaryl-C(0)O-, substituted heteroaryl-C(0)O-, heterocyclic-C(0)O-, and
substituted
heterocyclic-C(0)0- wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted
aryl, heteroaryl,
substituted heteroaryl, heterocyclic, and substituted heterocyclic are as
defined herein.
[0025] "Amino" refers to the group -NH2.
[0026] "Substituted amino" refers to the group _Nee where R21 and R22 are
independently
selected from the group consisting of hydrogen, alkyl, substituted alkyl,
alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,
substituted cycloalkyl,
heteroaryl, substituted heteroaryl, heterocyclic, substituted
heterocyclic, -502-alkyl, -502-substituted alkyl, -502-alkenyl,
-502-substituted alkenyl, -502-cycloalkyl, -502-substituted cylcoalkyl, -502-
aryl,
-502-substituted aryl, -502-heteroaryl, -502-substituted heteroaryl, -502-
heterocyclyl,
and -502-substituted heterocyclyl and wherein R21 and R22 are optionally
joined together with
the nitrogen bound thereto to form a heterocyclyl or substituted heterocyclyl
group, provided
that R21 and R22 are both not hydrogen, and wherein alkyl, substituted alkyl,
alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
aryl, substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
are as defined
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herein. When R21 is hydrogen and R22 is alkyl, the substituted amino group is
sometimes
referred to herein as alkylamino. When R21 and R22 are alkyl, the substituted
amino group is
sometimes referred to herein as dialkylamino. When referring to a
monosubstituted amino, it is
meant that either R21 or R22 is hydrogen but not both. When referring to a
disubstituted amino, it
is meant that neither R21 nor R22 are hydrogen.
[0027] "Hydroxyamino" refers to the group -NHOH.
[0028] "Alkoxyamino" refers to the group -NHO-alkyl wherein alkyl is defined
herein.
[0029] "Aminocarbonyl" refers to the group -C(0)NR23R24 where R23 and R24 are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted
heterocyclic, hydroxy,
alkoxy, substituted alkoxy, amino, substituted amino, and acylamino, and where
R23 and R24 are
optionally joined together with the nitrogen bound thereto to form a
heterocyclic or substituted
heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted
aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic are as
defined herein.
[0030] "Aminothiocarbonyl" refers to the group -C(S)NR23R24 where R23 and R24
are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic and
where R23 and R24 are optionally joined together with the nitrogen bound
thereto to form a
heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted
alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted
cycloalkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted heterocyclic are
as defined herein.
[0031] "Aminocarbonylamino" refers to the group -NR20c(0)N1R23¨x 24
where R2 is hydrogen
or alkyl and R23 and R24 are independently selected from the group consisting
of hydrogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, aryl,
substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted
heteroaryl,
heterocyclic, and substituted heterocyclic and where R23 and R24 are
optionally joined together
with the nitrogen bound thereto to form a heterocyclic or substituted
heterocyclic group, and
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wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl,
cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl,
heterocyclic and substituted heterocyclic are as defined herein.
[0032] "Aminothiocarbonylamino" refers to the group -NR20c(s)N1R23R24 where R2
is
hydrogen or alkyl and R23 and R24 are independently selected from the group
consisting of
hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, aryl,
substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted
heteroaryl,
heterocyclic, and substituted heterocyclic and where R23 and R24 are
optionally joined together
with the nitrogen bound thereto to form a heterocyclic or substituted
heterocyclic group, and
wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl,
cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl,
heterocyclic and substituted heterocyclic are as defined herein.
[0033] "Aminocarbonyloxy" refers to the group -0-C(0)NR 23R24 where R23 and
R24 are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic and
where R23 and R24 are optionally joined together with the nitrogen bound
thereto to form a
heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted
alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted
cycloalkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted heterocyclic are
as defined herein.
[0034] "Aminosulfonyl" refers to the group -S02NR23R24 where R23 and R24 are
independently
selected from the group consisting of hydrogen, alkyl, substituted alkyl,
alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,
substituted cycloalkyl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
and where R23 and
R24 are optionally joined together with the nitrogen bound thereto to form a
heterocyclic or
substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,
substituted alkenyl,
alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,
substituted aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic are as
defined herein.
[0035] "Aminosulfonyloxy" refers to the group -0-S02NR23R24 where R23 and R24
are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkenyl,

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substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic and
where R23 and R24 are optionally joined together with the nitrogen bound
thereto to form a
heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted
alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted
cycloalkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted heterocyclic are
as defined herein.
[0036] "Aminosulfonylamino" refers to the group -NR20_s02NR23¨x 24
where R2 is hydrogen
or alkyl and R23 and R24 are independently selected from the group consisting
of hydrogen,
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, aryl,
substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted
heteroaryl,
heterocyclic, and substituted heterocyclic and where R23 and R24 are
optionally joined together
with the nitrogen bound thereto to form a heterocyclic or substituted
heterocyclic group, and
wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl,
cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl,
heterocyclic and substituted heterocyclic are as defined herein.
[0037] "Amidino" refers to the group -C(=NR25)NR23¨ 24
K where R25, R23, and R24 are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
cycloalkyl, substituted
cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic and
where R23 and R24 are optionally joined together with the nitrogen bound
thereto to form a
heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted
alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted
cycloalkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted heterocyclic are
as defined herein.
[0038] "Aryl" refers to an aromatic group of from 6 to 14 carbon atoms and no
ring
heteroatoms and having a single ring (e.g., phenyl) or multiple condensed
(fused) rings (e.g.,
naphthyl or anthryl). For multiple ring systems, including fused, bridged, and
spiro ring systems
having aromatic and non-aromatic rings that have no ring heteroatoms, the term
"Aryl" or "Ar"
applies when the point of attachment is at an aromatic carbon atom (e.g.,
5,6,7,8
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tetrahydronaphthalene-2-y1 is an aryl group as its point of attachment is at
the 2-position of the
aromatic phenyl ring).
[0039] "Substituted aryl" refers to aryl groups which are substituted with 1
to 8 and, in some
embodiments, 1 to 5, 1 to 3 or 1 to 2 substituents selected from the group
consisting of alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
alkoxy, substituted
alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl,
aminothiocarbonyl,
aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,
aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,
aryloxy, substituted
aryloxy, arylthio, substituted arylthio, azido, carboxyl, carboxyl ester,
(carboxyl ester)amino,
(carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy,
substituted
cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino,
substituted guanidino, halo,
hydroxy, hydroxyamino, alkoxyamino, hydrazino, substituted hydrazino,
heteroaryl, substituted
heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio,
substituted heteroarylthio,
heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted
heterocyclyloxy,
heterocyclylthio, substituted heterocyclylthio, nitro, 503H, substituted
sulfonyl, sulfonyloxy,
thioacyl, thiocyanate, thiol, alkylthio, and substituted alkylthio, wherein
said substituents are
defined herein.
[0040] "Arylalkyl" or "Aryl(Ci-Cz)alkyl" refers to the radical ¨Rultv where le
is an alkylene
group (having eight or fewer main chain carbon atoms) and Ity is an aryl group
as defined
herein. Thus, "arylalkyl" refers to groups such as, for example, benzyl, and
phenylethyl, and the
like. Similarly, "Arylalkenyl" means a radical ¨leity where le is an
alkenylene group (an
alkylene group having one or two double bonds) and Ity is an aryl group as
defined herein, e.g.,
styrenyl, 3-phenyl-2-propenyl, and the like.
[0041] "Aryloxy" refers to the group -0-aryl, where aryl is as defined herein,
that includes, by
way of example, phenoxy and naphthoxy.
[0042] "Substituted aryloxy" refers to the group -0-(substituted aryl) where
substituted aryl is
as defined herein.
[0043] "Arylthio" refers to the group -S-aryl, where aryl is as defined
herein.
[0044] "Substituted arylthio" refers to the group -S-(substituted aryl), where
substituted aryl is
as defined herein.
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[0045] "Azido" refers to the group -N3.
[0046] "Hydrazino" refers to the group -NHNH2.
[0047] "Substituted hydrazino" refers to the group -N1R26NR27-28
where R26, R27, and R28 are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
carboxyl ester,
cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,
heterocyclic, substituted
heterocyclic, -502-alkyl, -502-substituted alkyl, -502-alkenyl,
-502-substituted alkenyl, -502-cycloalkyl, -502-substituted cylcoalkyl, -502-
aryl,
-502-substituted aryl, -502-heteroaryl, -502-substituted heteroaryl, -502-
heterocyclic,
and -502-substituted heterocyclic and wherein R27 and R28 are optionally
joined, together with
the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic
group, provided
that R27 and R28 are both not hydrogen, and wherein alkyl, substituted alkyl,
alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl,
substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, heterocyclic,
and substituted heterocyclic are as defined herein.
[0048] "Cyano" or "carbonitrile" refers to the group -CN.
[0049] "Carbonyl" refers to the divalent group -C(0)- which is equivalent to -
C(=0)-.
[0050] "Carboxyl" or "carboxy" refers to -COOH or salts thereof.
[0051] "Carboxyl ester" or "carboxy ester" refers to the groups -C(0)0-alkyl,
-C(0)0-substituted alkyl, -C(0)0-alkenyl, -C(0)0-substituted alkenyl, -C(0)0-
alkynyl,
-C(0)0-substituted alkynyl, -C(0)0-aryl, -C(0)0-substituted aryl, -C(0)0-
cycloalkyl,
-C(0)0-substituted cycloalkyl, -C(0)0-heteroaryl, -C(0)0-substituted
heteroaryl, -C(0)0-heterocyclic, and -C(0)0-substituted heterocyclic wherein
alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
substituted
cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic, and substituted
heterocyclic are as defined herein.
[0052] "(Carboxyl ester)amino" refers to the group _N1R20 -C(0)0-alkyl,
-NR20-C(0)0-substituted alkyl, -NR20-C(0)0-alkenyl, -NR20-C(0)0-substituted
alkenyl, -NR 2 -C(0)0-alkynyl, -NR20-C(0)0-substituted alkynyl, -NR20-C(0)0-
aryl,
-NR20-C(0)0-substituted aryl, -NR20-C(0)0-cycloalkyl, -NR20-C(0)0-substituted
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NR2o-C _NR2o-C(0)0-
cycloalkyl, - (0)0-heteroaryl, substituted heteroaryl,
-NR20-C(0)0-heterocyclic, and -NR20-C(0)0-substituted heterocyclic wherein R2
is alkyl or
hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, substituted
alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,
heteroaryl, substituted
heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0053] "(Carboxyl ester)oxy" refers to the group -0-C(0)0-alkyl, -0-C(0)0-
substituted
alkyl, -0-C(0)0-alkenyl, -0-C(0)0-substituted alkenyl, -0-C(0)0-alkynyl,
-0-C(0)0-substituted alkynyl, -0-C(0)0-aryl, -0-C(0)0-substituted aryl,
-0-C(0)0-cycloalkyl, -0-C(0)0-substituted cycloalkyl, -0-C(0)0-heteroaryl,
-0-C(0)0-substituted heteroaryl, -0-C(0)0-heterocyclic, and -0-C(0)0-
substituted
heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl, substituted
alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted heterocyclic are
as defined herein.
[0054] "Cycloalkyl" refers to a saturated or partially saturated cyclic group
of from 3 to 14
carbon atoms and no ring heteroatoms and having a single ring or multiple
rings including fused,
bridged, and spiro ring systems. For multiple ring systems having aromatic and
non-aromatic
rings that have no ring heteroatoms, the term "cycloalkyl" applies when the
point of attachment
is at a non-aromatic carbon atom (e.g., 5,6,7,8,-tetrahydronaphthalene-5-y1).
The term
"cycloalkyl" includes cycloalkenyl groups. Examples of cycloalkyl groups
include, for instance,
adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and cyclohexenyl.
"Cõcycloalkyl" refers to cycloalkyl groups having u to v carbon atoms as ring
members.
"Cõcycloalkenyl" refers to cycloalkenyl groups having u to v carbon atoms as
ring members.
[0055] "Cycloalkenyl" refers to a partially saturated cycloalkyl ring having
at least one site of
>C=C ring unsaturation.
[0056] "Substituted cycloalkyl" refers to a cycloalkyl group, as defined
herein, having from 1
to 8, or 1 to 5, or in some embodiments 1 to 3 substituents selected from the
group consisting of
oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl,
alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted
amino, aminocarbonyl,
aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy,
aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,
substituted aryl, aryloxy,
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substituted aryloxy, arylthio, substituted arylthio, azido, carboxyl, carboxyl
ester, (carboxyl
ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl,
cycloalkyloxy,
substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio,
guanidino, substituted
guanidino, halo, hydroxy, hydroxyamino, alkoxyamino, hydrazino, substituted
hydrazino,
heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy,
heteroarylthio,
substituted heteroarylthio, heterocyclic, substituted heterocyclic,
heterocyclyloxy, substituted
heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H,
substituted
sulfonyl, sulfonyloxy, thioacyl, thiocyanate, thiol, alkylthio, and
substituted alkylthio, wherein
said substituents are as defined herein. The term "substituted cycloalkyl"
includes substituted
cycloalkenyl groups.
[0057] "Cycloalkyloxy" refers to -0-cycloalkyl wherein cycloalkyl is as
defined herein.
[0058] "Substituted cycloalkyloxy" refers to -0-(substituted cycloalkyl)
wherein substituted
cycloalkyl is as defined herein.
[0059] "Cycloalkylthio" refers to -S-cycloalkyl wherein substituted cycloalkyl
is as defined
herein.
[0060] "Substituted cycloalkylthio" refers to -S-(substituted cycloalkyl)
wherein substituted
cycloalkyl is as defined herein.
[0061] "Guanidino" refers to the group -NHC(=NH)NH2.
[0062] "Substituted guanidino" refers to -NR29C(= NR29)N(R29)2 where each R29
is
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and
substituted heterocyclyl and
two R29 groups attached to a common guanidino nitrogen atom are optionally
joined together
with the nitrogen bound thereto to form a heterocyclic or substituted
heterocyclic group,
provided that at least one R29 is not hydrogen, and wherein said substituents
are as defined
herein.
[0063] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo.
[0064] "Haloalkyl" refers to substitution of alkyl groups with 1 to 5 or in
some embodiments 1
to 3 halo groups, e.g., -CH2C1, -CH2F, -CH2Br, -CFC1Br, -CH2CH2C1,

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-CH2CH2F, -CF3, -CH2CF3, -CH2CC13, and the like, and further includes those
alkyl groups such
as perfluoroalkyl in which all hydrogen atoms are replaced by fluorine atoms.
[0065] "Haloalkoxy" refers to substitution of alkoxy groups with 1 to 5 or in
some
embodiments 1 to 3 halo groups, e.g., -0CH2C1, -OCH2F, -OCH2CH2Br, -0CH2CH2C1,
-0CF3, and the like.
[0066] "Hydroxy" or "hydroxyl" refers to the group -OH.
[0067] "Heteroalkyl" means an alkyl radical as defined herein with one, two or
three
substituents independently selected from cyano, -OR'', -NRxRY, and -S(0)Rz
(where n is an
integer from 0 to 2), with the understanding that the point of attachment of
the heteroalkyl
radical is through a carbon atom of the heteroalkyl radical. Rw is hydrogen,
alkyl, cycloalkyl,
cycloalkyl-alkyl, aryl, arylalkyl, alkoxycarbonyl, aryloxycarbonyl,
carboxamido, or mono- or di-
alkylcarbamoyl. Rx is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl or
arylalkyl. RY is
hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl,
alkoxycarbonyl, aryloxycarbonyl,
carboxamido, mono- or di-alkylcarbamoyl or alkylsulfonyl. Rz is hydrogen
(provided that n is
0), alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, amino, mono-
alkylamino, di-alkylamino,
or hydroxyalkyl. Representative examples include, for example, 2-hydroxyethyl,
2,3-
dihydroxypropyl, 2-methoxyethyl,
benzyloxymethyl, 2-cyanoethyl, and 2-methylsulfonyl-ethyl. For each of the
above, Rw, R', RY,
and Rz can be further substituted by amino, fluorine, alkylamino, di-
alkylamino, OH or alkoxy.
Additionally, the prefix indicating the number of carbon atoms (e.g., Ci-Cio)
refers to the total
number of carbon atoms in the portion of the heteroalkyl group exclusive of
the cyano, -OR'', -
NRxRY, or -S(0)õRz portions.
[0068] "Heteroaryl" refers to an aromatic group of from 1 to 14 carbon atoms
and 1 to 6
heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur
and includes a 5
to 18 member ring or ring system that includes a single ring (e.g.,
imidazoly1) or multiple rings
(e.g., benzimidazol-2-y1 and benzimidazol-6-y1). For multiple ring systems,
including fused,
bridged, and spiro ring systems having aromatic and non-aromatic rings, the
term "heteroaryl"
applies if there is at least one ring heteroatom and the point of attachment
is at an atom of an
aromatic ring (e.g., 1,2,3,4-tetrahydroquinolin-6-y1 and 5,6,7,8-
tetrahydroquinolin-3-y1). In
some embodiments the nitrogen and/or the sulfur ring atom(s) of the heteroaryl
group are
optionally oxidized to provide for the N-oxide (N¨>0), sulfinyl, or sulfonyl
moieties. More
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specifically the term heteroaryl includes, but is not limited to, pyridyl,
furanyl, thienyl, thiazolyl,
isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl,
pyridazinyl, pyrimidinyl,
benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl,
benzoisothiazolyl,
benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl,
tetrahydroquinolinyl, isoquinolyl,
quinazolinonyl, benzimidazolyl, benzisoxazolyl, or benzothienyl.
[0069] "Substituted heteroaryl" refers to heteroaryl groups that are
substituted with from 1 to
8, or in some embodiments 1 to 5, or 1 to 3, or 1 to 2 substituents selected
from the group
consisting of the substituents defined for substituted aryl.
[0070] "Heteroaryloxy" refers to -0-heteroaryl wherein heteroaryl is as
defined herein.
[0071] "Substituted heteroaryloxy" refers to the group -0-(substituted
heteroaryl) wherein
heteroaryl is as defined herein.
[0072] "Heteroarylthio" refers to the group -S-heteroaryl wherein heteroaryl
is as defined
herein.
[0073] "Substituted heteroarylthio" refers to the group -S-(substituted
heteroaryl) wherein
heteroaryl is as defined herein.
[0074] "Heterocycle" or "heterocyclic" or "heterocyclo" or "heterocycloalkyl"
or
"heterocycly1" refers to a saturated or partially saturated cyclic group
having from 1 to 14
carbon atoms and from 1 to 6 heteroatoms selected from the group consisting of
nitrogen, sulfur,
or oxygen and includes single ring and multiple ring systems including fused,
bridged, and spiro
ring systems. For multiple ring systems having aromatic and/or non-aromatic
rings, the term
"heterocyclic", "heterocycle", "heterocyclo", "heterocycloalkyl" or
"heterocycly1" applies when
there is at least one ring heteroatom and the point of attachment is at an
atom of a non-aromatic
ring (e.g., 1,2,3,4-tetrahydroquinoline-3-yl, 5,6,7,8-tetrahydroquinoline-6-
yl, and
decahydroquinolin-6-y1). In some embodiments, the nitrogen and/or sulfur
atom(s) of the
heterocyclic group are optionally oxidized to provide for the N-oxide,
sulfinyl, and sulfonyl
moieties. More specifically the heterocyclyl includes, but is not limited to,
tetrahydropyranyl,
piperidinyl,
N-methylpiperidin-3-yl, piperazinyl, N-methylpyrrolidin-3-yl, 3-pyrrolidinyl,
2-pyrrolidon-1-yl, morpholinyl, and pyrrolidinyl. A prefix indicating the
number of carbon
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atoms (e.g., C3-C10) refers to the total number of carbon atoms in the portion
of the heterocyclyl
group exclusive of the number of heteroatoms.
[0075] "Substituted heterocycle" or "substituted heterocyclic" or "substituted
heterocyclo" or
"substituted heterocycloalkyl" or "substituted heterocyclyl" refers to
heterocyclic groups, as
defined herein, that are substituted with from 1 to 5 or in some embodiments 1
to 3 of the
substituents as defined for substituted cycloalkyl.
[0076] "Heterocyclyloxy" refers to the group -0-heterocyclyl wherein
heterocyclyl is as
defined herein.
[0077] "Substituted heterocyclyloxy" refers to the group -0-(substituted
heterocyclyl) wherein
heterocyclyl is as defined herein.
[0078] "Heterocyclylthio" refers to the group -S-heterocycyl wherein
heterocyclyl is as
defined herein.
[0079] "Substituted heterocyclylthio" refers to the group -S-(substituted
heterocycyl) wherein
heterocyclyl is as defined herein.
[0080] Examples of heterocycle and heteroaryl groups include, but are not
limited to,
azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine,
pyridazine, indolizine,
isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline,
quinoline,
phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,
carbazole,
carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine,
isoxazole,
phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine,
piperazine, indoline,
phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-
tetrahydrobenzo[b]thiophene, thiazole,
thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also
referred to as
thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and
tetrahydrofuranyl.
[0081] "Nitro" refers to the group -NO2.
[0082] "Oxo" refers to the atom (=0).
[0083] "Oxide" refers to products resulting from the oxidation of one or more
heteroatoms.
Examples include N-oxides, sulfoxides, and sulfones.
[0084] "Spirocycloalkyl" refers to a 3 to 10 member cyclic substituent formed
by replacement
of two hydrogen atoms at a common carbon atom with an alkylene group having 2
to 9 carbon
23

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atoms, as exemplified by the following structure wherein the methylene group
shown below
attached to bonds marked with wavy lines is substituted with a spirocycloalkyl
group:
X
[0085] "Sulfonyl" refers to the divalent group -S(0)2-.
[0086] "Substituted sulfonyl" refers to the group -502-alkyl, -502-substituted
alkyl,
-502-alkenyl, -502-substituted alkenyl, -502-alkynyl, -502-substituted
alkynyl,
-502-cycloalkyl, -502-substituted cylcoalkyl, -502-aryl, -502-substituted
aryl,
-502-heteroaryl, -502-substituted heteroaryl, -502-heterocyclic, -502-
substituted heterocyclic,
wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl,
cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl,
heterocyclic and substituted heterocyclic are as defined herein. Substituted
sulfonyl includes
groups such as methyl- SO2-, phenyl-502-, and 4-methylpheny1-502-.
[0087] "Sulfonyloxy" refers to the group -0502-alkyl, -0502-substituted alkyl,
-0502-alkenyl, -0502-substituted alkenyl, -0502-cycloalkyl, -0502-substituted
cylcoalkyl, -0502-aryl, -0502-substituted aryl, -0502-heteroaryl, -0502-
substituted
heteroaryl, -0502-heterocyclic, -0502-substituted heterocyclic, wherein alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
substituted cycloalkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
substituted heterocyclic are
as defined herein.
[0088] "Thioacyl" refers to the groups H-C(S)-, alkyl-C(5)-, substituted alkyl-
C(5)-,
alkenyl-C(5)-, substituted alkenyl-C(5)-, alkynyl-C(5)-, substituted alkynyl-
C(5)-,
cycloalkyl-C(5)-, substituted cycloalkyl-C(5)-, aryl-C(5)-, substituted aryl-
C(5)-,
heteroaryl-C(5)-, substituted heteroaryl-C(5)-, heterocyclic-C(5)-, and
substituted
heterocyclic-C(5)-, wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted
aryl, heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic are as
defined herein.
[0089] "Thiol" refers to the group -SH.
[0090] "Alkylthio" refers to the group -5-alkyl wherein alkyl is as defined
herein.
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[0091] "Substituted alkylthio" refers to the group -S-(substituted alkyl)
wherein substituted
alkyl is as defined herein.
[0092] "Thiocarbonyl" refers to the divalent group -C(S)- which is equivalent
to -C(=5)-.
[0093] "Thione" refers to the atom (=S).
[0094] "Thiocyanate" refers to the group -SCN.
[0095] "Compound" and "compounds" as used herein refers to a compound
encompassed by
the generic formulae disclosed herein, any subgenus of those generic formulae,
and any forms of
the compounds within the generic and subgeneric formulae, such as an oxide,
ester, prodrug,
pharmaceutically acceptable salt, or solvate. Unless specified otherwise, the
term further
includes the racemates, stereoisomers, and tautomers of the compound or
compounds.
[0096] "Racemates" refers to a mixture of enantiomers.
[0097] "Solvate" or "solvates" of a compound refer to those compounds, where
compounds
are as defined above, that are bound to a stoichiometric or non-stoichiometric
amount of a
solvent. Solvates of a compound includes solvates of all forms of the compound
such as the
oxide, ester, prodrug, or pharmaceutically acceptable salt of the disclosed
generic and
subgeneric formulae. Preferred solvents are volatile, non-toxic, and/or
acceptable for
administration to humans.
[0098] "Stereoisomer" or "stereoisomers" refer to compounds that differ in the
chirality of one
or more stereocenters. Stereoisomers include enantiomers and diastereomers.
The compounds
disclosed herein may exist in stereoisomeric form if they possess one or more
asymmetric
centers or a double bond with asymmetric substitution and, therefore, can be
produced as
individual stereoisomers or as mixtures. Unless otherwise indicated, the
description is intended
to include individual stereoisomers as well as mixtures. The methods for the
determination of
stereochemistry and the separation of stereoisomers are well-known in the art
(see discussion in
Chapter 4 of Advanced Organic Chemistry, 4th edition J. March, John Wiley and
Sons, New
York, 1992).
[0099] "Tautomer" refers to alternate forms of a compound that differ in the
position of a
proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms
of heteroaryl

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groups containing a ring atom attached to both a ring -NH- moiety and a ring
=N- moiety such
as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
[0100] "Prodrug" refers to any derivative of a compound of the embodiments
that is capable of
directly or indirectly providing a compound of the embodiments or an active
metabolite or
residue thereof when administered to a patient. Prodrugs of a compound
disclosed herein are
prepared by modifying functional groups present in the compound in such a way
that the
modifications may be cleaved in vivo to release the parent compound, or an
active metabolite.
For example, prodrugs include compounds wherein a hydroxy, amino, or
sulfhydryl group in a
compound I is bonded to any group that may be cleaved in vivo to regenerate
the free hydroxyl,
amino, or sulfhydryl group, respectively. Particularly favored derivatives and
prodrugs are those
that increase the bioavailability of the compounds of the embodiments when
such compounds
are administered to a patient (e.g., by allowing an orally administered
compound to be more
readily absorbed into the blood) or which enhance delivery of the parent
compound to a
biological compartment (e.g., the brain or lymphatic system) relative to the
parent species.
Prodrugs include ester, amide, and carbamate (e.g., N, N-
dimethylaminocarbonyl) forms of
hydroxy functional groups of compounds disclosed herein. Examples of ester
prodrugs include
formate, acetate, propionate, butyrate, acrylate, and ethylsuccinate
derivatives. An general
overview of prodrugs is provided in T Higuchi and V Stella, Pro-drugs as Novel
Delivery
Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B Roche, ed.,
Bioreversible
Carriers in Drug Design, American Pharmaceutical Association and Pergamon
Press, 1987, both
of which are incorporated herein by reference.
[0101] "Pharmaceutically acceptable salt" refers to pharmaceutically
acceptable salts derived
from a variety of organic and inorganic counter ions well known in the art and
includes, by way
of example only, sodium, potassium, calcium, magnesium, ammonium, and
tetraalkylammonium. When the molecule contains a basic functionality, acid
addition salts of
organic or inorganic acids, such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric
acid, phosphoric acid, and the like; or formed with organic acids such as
acetic acid, propionic
acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,
lactic acid, malonic
acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid,
citric acid, benzoic acid,
3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid,
ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic
acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, oxalic acid, 4-
toluenesulfonic
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acid, camphorsulfonic acid, methanesulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-
ene-1-
carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic
acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid,
salicylic acid, stearic acid, muconic acid, and the like. Salts can also be
formed when an acidic
proton present in the parent compound is either replaced by a metal ion, e.g.,
an alkali metal ion,
an alkaline earth ion, or an aluminum ion; or coordinates with an organic base
such as
ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-
methylglucamine, and the
like. Pharmaceutically acceptable salts are suitable for administration in a
patient and possess
desirable pharmacological properties. Suitable salts further include those
described in P.
Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts
Properties,
Selection, and Use; 2002.
[0102] Unless indicated otherwise, the nomenclature of substituents that are
not explicitly
defined herein are arrived at by naming the terminal portion of the
functionality followed by the
adjacent functionality toward the point of attachment. For example, the
substituent
"arylalkyloxycabonyl" refers to the group (aryl)-(alkyl)-0-C(0)-.
[0103] It is understood that in all substituted groups defined above, polymers
arrived at by
defining substituents with further substituents to themselves (e.g.,
substituted aryl having a
substituted aryl group as a sub stituent which is itself substituted with a
substituted aryl group,
which is further substituted by a substituted aryl group, etc.) are not
intended for inclusion
herein. In such cases, the maximum number of such substitutions is three. For
example, serial
substitutions of substituted aryl groups with two other substituted aryl
groups are limited
to -substituted aryl-(substituted aryl)-substituted aryl.
[0104] Similarly, it is understood that the above definitions are not intended
to include
impermissible substitution patterns (e.g., methyl substituted with 5 fluor
groups). Such
impermissible substitution patterns are well known to the skilled artisan.
[0105] The terms "optional" or "optionally" as used throughout the
specification means that
the subsequently described event or circumstance may but need not occur, and
that the
description includes instances where the event or circumstance occurs and
instances in which it
does not. For example, "heterocyclo group optionally mono- or di- substituted
with an alkyl
group" means that the alkyl may but need not be present, and the description
includes situations
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where the heterocyclo group is mono- or disubstituted with an alkyl group and
situations where
the heterocyclo group is not substituted with the alkyl group.
[0106] Turning next to the compositions disclosed herein, the term
"pharmaceutically
acceptable carrier or excipient" means a carrier or excipient that is useful
in preparing a
pharmaceutical composition that is generally safe, possesses acceptable
toxicities. Acceptable
carriers or excipients include those that are acceptable for veterinary use as
well as human
pharmaceutical use. A "pharmaceutically acceptable carrier or excipient" as
used in the
specification and claims includes both one and more than one such carrier or
excipient.
[0107] With reference to the methods disclosed herein, the following terms are
used with the
noted meanings:
[0108] The terms "treating" or "treatment" of a disease or condition includes:
(1) preventing or reducing the risk of developing the disease or condition,
i.e.,
causing the clinical symptoms of the disease or condition not to develop in a
mammal that may
be exposed to or predisposed to the disease or condition but does not yet
experience or display
symptoms of the disease or condition,
(2) inhibiting the disease or condition, i.e., arresting or reducing the
development of
the disease or condition, or its clinical symptoms, or
(3) relieving the disease or condition, i.e., causing regression of the
disease or
condition, or its clinical symptoms,
or any combination of two or more thereof.
[0109] A preferred embodiment is treatment of a disease or condition that
consists of relieving
the disease or condition.
[0110] The term "diagnosing" refers to determining the presence or absence of
a particular
disease or condition. Additionally, the term refers to determining the level
or severity of a
particular disease or condition, as well as monitoring of the disease or
condition to determine its
response to a particular therapeutic regimen.
[0111] The term "therapeutically effective amount" means the amount of the
subject
compound that will elicit the biological or medical response of a tissue,
system, animal or
human that is being sought by the researcher, veterinarian, medical doctor or
other clinician. "A
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therapeutically effective amount" includes the amount of a compound that, when
administered to
a mammal for treating a disease or condition, is sufficient to effect such
treatment for the disease
or condition. The "therapeutically effective amount" will vary depending on
the compound, the
disease or condition, and its severity, and the age, weight, etc., of the
mammal to be treated.
[0112] "Patient" refers to mammals and includes humans and non-human mammals.
Examples of patients include, but are not limited to mice, rats, hamsters,
guinea pigs, pigs,
rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, the
term "subject" is
used interchangeably with "patient".
[0113] The term "mammal" includes, without limitation, humans, domestic
animals (e.g., dogs
or cats), farm animals (cows, horses, or pigs), and laboratory animals (mice,
rats, hamsters,
guinea pigs, pigs, rabbits, dogs, or monkeys).
[0114] The term "agonist" refers to a compound that binds to a receptor and
triggers a
response in a cell. An agonist mimics the effect of an endogenous ligand, a
hormone for
example, and produces a physiological response similar to that produced by the
endogenous
ligand.
[0115] The term "partial agonist" refers to a compound that binds to a
receptor and triggers a
partial response in a cell. A partial agonist produces only a partial
physiological response of the
endogenous ligand.
[0116] Glucagon-like peptide-2 (GLP-2) is a 33-amino acid peptide, co-secreted
with GLP-1
from intestinal endocrine cells in the small and large intestine.
[0117] GPR119 is a G protein-coupled receptor mainly found on enteroendocrine
K and L
cells and on pancreatic islets.
[0118] Provided herein, in one aspect, are methods of treating an inflammatory
gastrointestinal
disease or a gastrointestinal condition involving malabsorption of nutrients
and/or fluids in a
patient in need thereof, the methods comprising administering to the patient a
therapeutically
effective amount of a GPR119 agonist.
[0119] In another aspect, provided herein are methods of treating an
inflammatory
gastrointestinal disease or a gastrointestinal condition involving
malabsorption of nutrients
and/or fluids in a patient in need thereof, the methods comprising
administering to the patient a
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therapeutically effective amount of a GPR119 agonist and a therapeutically
effective amount of
a DPP IV inhibitor.
[0120] In another aspect, provided herein are methods of treating an
inflammatory
gastrointestinal disease or a gastrointestinal condition involving
malabsorption of nutrients
and/or fluids in a patient in need thereof, the methods comprising
administering to the patient a
therapeutically effective amount of a GPR119 agonist, a therapeutically
effective amount of a
DPP IV inhibitor, and a therapeutically effective amount of metformin.
[0121] Illustrative inflammatory gastrointestinal diseases or gastrointestinal
condition s
involving malabsorption of nutrients and/or fluids include, but are not
limited to, short bowel
syndrome (SBS), inflammatory bowel disease (IBD), Crohn's disease, ulcerative
colitis,
volvulus, and necrotizing enterocolitis. In some embodiments, the inflammatory
gastrointestinal
disease or the gastrointestinal condition involving malabsorption of nutrients
and/or fluids is
short bowel syndrome. In some embodiments, the inflammatory gastrointestinal
disease or the
gastrointestinal condition involving malabsorption of nutrients and/or fluids
is inflammatory
bowel disease. In some embodiments, the inflammatory gastrointestinal disease
or the
gastrointestinal condition involving malabsorption of nutrients and/or fluids
is Crohn's disease
or ulcerative colitis. In some embodiments, the inflammatory gastrointestinal
disease or the
gastrointestinal condition involving malabsorption of nutrients and/or fluids
is Crohn's disease.
In some embodiments, the inflammatory gastrointestinal disease or the
gastrointestinal condition
involving malabsorption of nutrients and/or fluids is ulcerative colitis. In
some embodiments,
the inflammatory gastrointestinal disease or the gastrointestinal condition
involving
malabsorption of nutrients and/or fluids is volvulus. In some embodiments, the
inflammatory
gastrointestinal disease or the gastrointestinal condition involving
malabsorption of nutrients
and/or fluids is necrotizing enterocolitis.
[0122] In some embodiments, the GPR119 agonists are compounds of Formula (I),
represented by the following:
x¨Y
R1 NA U (R7)p
( R2 )q
(I)

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wherein the letters X, Y, and Z are each independently selected from the group

consisting of 0, N, NIR8, S, and C(R3) and at least one of X, Y, and Z is 0,
N, Nle, or S; J, K, T,
and U are each independently selected from the group consisting of C, CH, and
N; the subscript
p is an integer of from 0 to 4; and the subscript q is an integer of from 0 to
4.
[0123] In Formula (I), RI- is a member selected from the group consisting of
H, Ci_ioalkyl, C1-
iosubstituted alkyl, C3_7cycloalkyl, C2_10alkenyl, C2.10alkynyl, -Xl-CORa,
-Xl-0O21e, -Xl-CONRaltb, -SO2Ra, a 4- to 7-membered heterocyclo group, aryl
and a 5- to 10-
membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo
group, aryl
group and heteroaryl group is optionally substituted with from 1 to 4
substituents independently
selected from halo, Ci_loalkyl, Ci_iosubstituted alkyl, C3_7cycloalkyl,
C2_10 alkenyl, C2.10alkynyl, aryl, heteroaryl, -CN, -NRaCORb, -NRaCONRaRb, -
NO2,
-0Ra, -NRaRb, -CORa, -CO2Ra, -CONRaRb, -S(0)Ra, -NRaS(0)2Rb, and -SO2NRaRb, or

optionally Ra and Rb are combined to form a 4-, 5- or 6-membered ring, and Xl
is selected from
the group consisting of a bond, C2.6alkene, C2_6alkyne, -C(0)-, and -C(0)-
(CH2)1.4-, wherein the
aliphatic portions of Xl are optionally substituted with one to three members
selected from
halogen, Ci.4alkyl, Ci4substituted alkyl and Ci.4haloalkyl.
[0124] Turning next to R2, each R2 is a member independently selected from the
group
consisting of halogen, C1.5 alkyl, C1.5substituted alkyl, C3_7cycloalkyl, -
CORa, -CO2Ra,
-CONRaRb, -0Ra, -NRaRb, -NRaCORb, -SORaRb, -SO2Ra and -SO2NRaRb, and wherein
when
the subscript q is 2 and R2 is alkyl or substituted alkyl, the two R2 members
can optionally
cyclize to form a ring.
[0125] R3 is a member selected from the group consisting of hydrogen, halogen,

Ci.4alkyl, and Ci4haloalkyl.
[0126] Each R7 of Formula (I) is independently selected from the group
consisting of halo, C1.
Ci_iosubstituted alkyl, C3_7cycloalkyl, C2-ioalkenyl, C2.10alkynyl, -CN,
-NO2, -0Ra, -NRaRb, -CORa, -CO2Ra, -CONRaRb, -NRaCORb, -NRaCO2Rb,
-NRaCONRaRb, -S(0)Ra, -NRaS(0)Rb, -SO2NRaRb, a 4- to 7- membered heterocyclo
group,
aryl and a 5- to 10-membered heteroaryl group, wherein each of said
heterocyclo groups, said
aryl and heteroaryl groups are optionally substituted with from one to four
substituents
independently selected from halo, oxo, C1-4 alkyl, C1-4 haloalkyl,
C3.7 cycloalkyl, -CN, -NO2, -0Ra, -NRaRb, -CORa, -CO2Ra, -CONRaRb, -NRaCORb,
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-NRaCO2Rb, -NRaCONRaRb, -S(0)Ra, -NRaSO2Rb, and -SO2NRaRb and wherein the
subscript
m is an integer of from 0 to 2, or optionally Ra and Rb are combined to form a
4-, 5- or 6-
membered ring.
[0127] R8 is a member independently selected from the group consisting of
hydrogen,
Ci_4alkyl, and Ci4haloalkyl.
[0128] For each of the above groups, each Ra and Rb is independently selected
from the group
consisting of hydrogen, Ci_io alkyl, Ci_iohaloalkyl, C3.10cycloalkyl,
heterocyclyl, C2.10alkenyl,
C2.10alkynyl, aryl, 5- to 6-membered heteroaryl and ary1C1.4alkyl; and wherein
the aliphatic
portions of each of said Ra and Rb is optionally substituted with from one to
three members
selected from the group consisting of halo, -0r, -0C(0)N(R11)2,
- -S(0)1e, -S(0)21e, -S(0)2N(102, -NleS(0)21e, -C(0)N(102, -C(0)1e, -
NRI1C(0)1e, -NR
"C(0)N(102, -0O21e, -NRI1CO21e, -CN, -NO2, -N(102 and -NIVS(0)2N(102, wherein
each le
is independently hydrogen or an unsubstituted C1-6 alkyl; and wherein the aryl
and heteroaryl
portions are optionally substituted with from one to three members selected
from
halogen, -OR', -0C(0)N(Rm)2, -SR111, -S(0)R111, -S(0)2R111, -S(0)2N(Rm)2,
-NR'S(0)2Rm, -C(0)N(Rm)2, -C(0)Rm, -NRIIIC(0)Rm, -NRIIIC(0)N(Rm)2, -0O21e1,
-NIVICO2Rm, -CN, -NO2, -N(Rm)2 and -NR'S(0)2N(Rm)2, wherein each RI' is
independently
hydrogen or an unsubstituted C1.6 alkyl.
[0129] The compounds provided herein also include any pharmaceutically
acceptable salts of
the compounds as well as any isotopically labeled isomers thereof In general,
the compounds
useful in the methods described herein are those compound of the formula
above, wherein the
molecular weight of the compound is less than 1200, more preferably less than
about 1000, still
more preferably less than about 800 and still more preferably from about 200
to about 600.
[0130] In some embodiments, a le group is selected from the group consisting
of -Xl-CORa, -Xl-CO2Ra, -Xl-CONRaRb, -SO2Ra, aryl, heteroaryl, substituted
aryl and
substituted heteroaryl. In some embodiments, when le is an aromatic
substituent, le is selected
from the group consisting of pyridyl, substituted pyridyl, pyrimidinyl,
substituted pyrimidinyl,
pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl,
phenyl, substituted phenyl,
imidazolyl, triazolyl, substituted triazolyl, substituted imidazolyl,
oxazolyl, substituted oxazolyl,
thiazolyl, substituted thiazolyl, oxadiazolyl, substituted oxadiazolyl,
tetrazolyl, and substituted
tetrazolyl.
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[0131] In some embodiments, when le is an aromatic substituent, e.g., aryl or
heteroaryl, le is
substituted with from one to three substituents selected from the group
consisting of Ci_ioalkyl,
Ci_iohaloalkyl, C3_7cycloalkyl, aryl, heteroaryl, -NO2, _oRa, _NRaRb, _co2Ra,
-CONRaRb, -S(0)Ra, -NRaS(0)2Rb, and ¨SO2NRaRb.
[0132] In some embodiments, R2 is a member independently selected from the
group
consisting of halo, Ci_5alkyl, Ci_5haloalkyl, and the subscript q is an
integer of from 0 to 2.
[0133] In some embodiments, D is 0. In compounds of Formula (I), when D is 0,
a le group
is selected from the group consisting of -Xl-CORa, -Xl-CO2Ra, -Xl-CONRaRb,
-SO2Ra, aryl, heteroaryl, substituted aryl and substituted heteroaryl. In some
embodiments,
when le is an aromatic substituent, le is selected from the group consisting
of pyridyl,
substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl,
substituted pyrazinyl,
pyridazinyl, substituted pyridazinyl, phenyl, substituted phenyl, imidazolyl,
triazolyl, substituted
triazolyl, substituted imidazolyl, oxazolyl, substituted oxazolyl, thiazolyl,
substituted thiazolyl,
oxadiazolyl, substituted oxadiazolyl, tetrazolyl, and substituted tetrazolyl.
[0134] Additionally, in some embodiments, when D is 0, and le is an aromatic
substituent,
e.g., aryl or heteroaryl, le is substituted with from one to three
substituents selected from the
group consisting of Ci_ioalkyl, Cmohaloalkyl, C3_7cycloalkyl, aryl,
heteroaryl, -NO2, -OR
a, _NRaRb, _co2Ra, _coNRaRb, _s(0)mRa, _NRas(0)2Rb,
and ¨SO2NRaRb.
[0135] In some embodiments, J, K, T, and U are all C or CH. In further
embodiments, a le
group is selected from the group consisting of -Xl-CORa, -Xl-CO2Ra, -Xl-
CONRaRb,
-S02Ra, aryl, heteroaryl, substituted aryl and substituted heteroaryl. In some
embodiments,
when le is an aromatic substituent, le is selected from the group consisting
of pyridyl,
substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl,
substituted pyrazinyl,
pyridazinyl, substituted pyridazinyl, phenyl, substituted phenyl, imidazolyl,
triazolyl, substituted
triazolyl, substituted imidazolyl, oxazolyl, substituted oxazolyl, thiazolyl,
substituted thiazolyl,
oxadiazolyl, substituted oxadiazolyl, tetrazolyl, and substituted tetrazolyl.
In further
embodiments, when J, K, T, and U are all C or CH, and le is an aromatic
substituent, e.g., aryl
or heteroaryl, le is substituted with from one to three substituents selected
from the group
consisting of C moalkyl, Ci_iohaloalkyl, C3_7cycloalkyl, aryl,
33

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heteroaryl, -NO2, -0Ra, -NRaRb, -CO2Ra, -CONRaRb, -S(0)Ra, -NRaS(0)2Rb,
and -SO2NRaRb.
[0136] In some embodiments, the subscript p is an integer of from 1 to 3 and
each R7 is
independently selected from the group consisting of halo, Ci_ioalkyl,
Ci_iohaloalkyl,
-CN, -NO2, -0Ra, -NRaRb, -CORa, -CO2Ra, -CONRaRb, -NRaCORb, -NRaCO2Rb, -
S(0)mRa, -NR
aS(0)mRb, -SO2NRaRb, a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-
membered
heteroaryl group, wherein each of said heterocyclo groups, said aryl and
heteroaryl groups are
optionally substituted with from one to four substituents independently
selected from halo, oxo,
C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl,
-CN, -NO2, -0Ra, -NRaRb, -CO2Ra, -CONRaRb, -NRaCORb, -NRaCO2Rb,
-NRaSO2Rb, and -SO2NRaRb and wherein the subscript m is an integer of from 0
to 2.
[0137] In some embodiments, J, K, T, and U are all C or CH. In further
embodiments, a le
group is selected from the group consisting of -Xl-CORa, -Xl-CO2Ra, -Xl-
CONRaRb,
-S02Ra, aryl, heteroaryl, substituted aryl and substituted heteroaryl. In some
embodiments,
when le is an aromatic substituent, le is selected from the group consisting
of pyridyl,
substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl,
substituted pyrazinyl,
pyridazinyl, substituted pyridazinyl, phenyl, substituted phenyl, imidazolyl,
triazolyl, substituted
triazolyl, substituted imidazolyl, oxazolyl, substituted oxazolyl, thiazolyl,
substituted thiazolyl,
oxadiazolyl, substituted oxadiazolyl, tetrazolyl, and substituted tetrazolyl;
and the subscript p is
an integer of from 1 to 3 and each R7 is independently selected from the group
consisting of
halo, Ci_loalkyl, Ci_iohaloalkyl, -CN, -NO2,
-0Ra, -NRaRb, -CORa, -CO2Ra, -CONRaRb, -NRaCORb, -NRaCO2Rb, -S(0)mRa,
-NRaS(0)mRb, -SO2NRaRb, a 4- to 7-membered heterocyclo group, aryl and a 5- to
10-
membered heteroaryl group, wherein each of said heterocyclo groups, said aryl
and heteroaryl
groups are optionally substituted with from one to four substituents
independently selected from
halo, oxo, C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, -CN, -NO2,
-0Ra, -NRaRb, -CO2Ra, -CONRaRb, -NRaCORb, -NRaCO2Rb, -S(0)mRa, -NRaSO2Rb,
and -SO2NRaRb and wherein the subscript m is an integer of from 0 to 2.
Optionally, le is
substituted with from one to three substituents selected from the group
consisting of Ci_ioalkyl,
Ci_iohaloalkyl, C3_7cycloalkyl, aryl, heteroaryl, -NO2, -0Ra, -NRaRb, -CO2Ra,
-CONRaRb, -S(0)mRa, -NRaS(0)2Rb, and -SO2NRaRb.
34

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[0138] In some embodiments, at least one of J, K, T, and U is N. In further
embodiments, D is
0, S, or NR8.
[0139] In some embodiments, at least one of J, K, T, and U is N and D is 0.
[0140] In some embodiments, when at least one of J, K, T, and U is N and D is
0, a le group
is selected from the group consisting of -Xl-CORa, -Xl-CO2Ra, -Xl-CONRaRb,
-SO2Ra, aryl, heteroaryl, substituted aryl and substituted heteroaryl. In some
embodiments,
when le is an aromatic substituent, le is selected from the group consisting
of pyridyl,
substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl,
substituted pyrazinyl,
pyridazinyl, substituted pyridazinyl, phenyl, substituted phenyl, imidazolyl,
substituted
imidazolyl, triazolyl, substituted triazolyl, oxazolyl, substituted oxazolyl,
thiazolyl, substituted
thiazolyl, oxadiazolyl, substituted oxadiazolyl, tetrazolyl, and substituted
tetrazolyl; and the
subscript p is an integer of from 1 to 3 and each R7 is independently selected
from the group
consisting of halo, Ci_ioalkyl, Cmohaloalkyl, -CN, -NO2,
-0Ra, -NRaRb, -CORa, -CO2Ra, -CONRaRb, -NRaCORb, -NRaCO2Rb, -S(0)Ra,
-NRaS(0)mRb, -SO2NRaRb, a 4- to 7-membered heterocyclo group, aryl and a 5- to
10-
membered heteroaryl group, wherein each of said heterocyclo groups, said aryl
and heteroaryl
groups are optionally substituted with from one to four substituents
independently selected from
halo, oxo, C1_4 alkyl, C1.4 haloalkyl, C3.7 cycloalkyl, -CN,
-NO2, -0Ra, -NRaRb, -CO2Ra, -CONRaRb, -NRaCORb, -NRaCO2Rb, -S(0)mRa,
-NRaSO2Rb, and -SO2NRaRb and wherein the subscript m is an integer of from 0
to 2.
Optionally, le is substituted with from one to three substituents selected
from the group
consisting of Ci_loalkyl, Ci_iohaloalkyl, C3_7cycloalkyl, aryl, heteroaryl, -
NO2, -0Ra,
-NRaRb, -0O2Ra, -CONRaRb, -S(0)mRa, -NRaS(0)2Rb, and -SO2NRaRb.
[0141] In some embodiments, when at least one of J, K, T, and U is N and D is
0, and le is as
described in the above paragraph, the subscript p is an integer of from 1 to 3
and each R7 is
independently selected from the group consisting of halo, Ci_ioalkyl, C1-
iohaloalkyl, -CN, -NO2, -0Ra, -NRaRb, -CORa, -CO2Ra, -CONRaRb, -NRaCORb,
-NRaCO2Rb, -S(0)mRa, -NRaS(0)mRb, -SO2NRaRb, a 4- to 7-membered heterocyclo
group, aryl
and a 5- to 10-membered heteroaryl group, wherein each of said heterocyclo
groups, said aryl
and heteroaryl groups are optionally substituted with from one to four
substituents
independently selected from halo, oxo, C1_4 alkyl, Ci.4 haloalkyl, C3-7
cycloalkyl, -CN, -NO2,

CA 03032432 2019-01-29
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-0Ra, -NRaRb, -CO2Ra, -CONRaRb, -NRaCORb, -NRaCO2Rb, -S(0)mRa, -NRaSO2Rb,
and -SO2NRaRb and wherein the subscript m is an integer of from 0 to 2.
[0142] In some embodiments, J, T, and U are all C or CH, and D is 0, S, or
NR8.
[0143] In some embodiments, J, T, and U are all C or CH, and D is 0.
[0144] In some embodiments, when J, T, and U are all C or CH, and D is 0, the
R7 group is a
member independently selected from the group consisting of halo, C1.10 alkyl,
Ci_io haloalkyl, -CN, -NO2, -0Ra, -NRaRb, -CORa, -CO2Ra, -CONRaRb, -NRaCORb,
-NRaCO2Rb, -S(0)mRa, -NRaS(0)mRb, -SO2NRaRb, a 4- to 5-membered heterocyclo
group, and a
5- to 6-membered heteroaryl group and wherein the subscript m is an integer of
from 0 to 2. In
some embodiments, R7 groups are independently selected from the group
consisting of halo, Ci.
alkyl, C 1-5 haloalkyl, -SORa, -SO2Ra, and 5-membered heteroaryl group. In
further
embodiments, R7 groups are independently selected from the group consisting of
fluor , chloro,
methyl, ethyl, -CF3, -S02CH3, imidazolyl, triazolyl, and tetrazolyl and
wherein the subscript p is
integer of from 1 to 2.
[0145] In some embodiments, when J, T, and U are all C or CH, and D is 0, the
R7 group is a
member independently selected from the group consisting of halo, C1.10 alkyl,
C1-10
haloalkyl, -CN, -NO2, -0Ra, -NRaRb, -CORa, -CO2Ra, -CONRaRb, -NRaCORb, -
NRaCO2Rb, -S(0
)mRa, -NRaS(0)mRb, -SO2NRaRb, a 4- to 5-membered heterocyclo group, and a 5-
to 6-membered
heteroaryl group and wherein the subscript m is an integer of from 0 to 2, and
each R2 is a
member independently selected from the group consisting of halo, Ci_5alkyl,
Ci_5haloalkyl, and
the subscript q is an integer of from 0 to 2. In some embodiments, R7 groups
are independently
selected from the group consisting of halo, Ci_5alkyl, Ci_5haloalkyl, -SORa, -
SO2Ra, and 5-
membered heteroaryl group. In further embodiments, R7 groups are independently
selected from
the group consisting of fluor , chloro, methyl, ethyl, -CF3, -S02C1.3alkyl,
imidazolyl, triazolyl,
and tetrazolyl and wherein the subscript p is integer of from 1 to 2.
[0146] In some embodiments, when J, T, and U are all C or CH, and D is 0, the
R7 group is a
member as described above, and R1 is selected from the group consisting of -Xl-
CORa,
-X1CO2Ra, -Xl-CONRaRb, -SO2Ra, aryl, heteroaryl, substituted aryl and
substituted heteroaryl.
In some embodiments, R1 group is selected from the group consisting of is
aryl, heteroaryl,
substituted aryl and substituted heteroaryl. In further embodiments, R1 is
selected from the
group consisting of pyridyl, substituted pyridyl, pyrimidinyl, substituted
pyrimidinyl, pyrazinyl,
36

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substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, phenyl,
substituted phenyl,
imidazolyl, triazolyl, substituted triazolyl, substituted imidazolyl,
oxazolyl, substituted oxazolyl,
thiazolyl, substituted thiazolyl, oxadiazolyl, substituted oxadiazolyl,
tetrazolyl, and substituted
tetrazolyl. In still further embodiments, le is selected from the group
consisting of pyrimidinyl,
substituted pyrimidinyl, oxadiazolyl, substituted oxadiazolyl, and -Xl-0O21e
and wherein Xl is
a bond.
[0147] In some embodiments, J, T, and U are all C or CH; and D is 0, X is S, Y
is C, Z is N;
R' is selected from the group consisting of pyrimidinyl, substituted
pyrimidinyl, pyridyl, and
substituted pyridyl, each R7 is independently selected from the group
consisting of fluor and
tetrazolyl.
[0148] Compounds of Formula (I) are shown in the example section herein.
Preferred
compounds of Formula (I) are the compounds of examples 1-210. Even more
preferred
compounds of Formula (I) are the compounds of examples 52, 76, 77, 95, 148,
162, 170, 171,
182, 184, 185, and 195.
[0149] In particular, a preferred compound of Formula (I) is
N/Th
N N 0 110
NN
r(l
N
or a pharmaceutically acceptable salt thereof.
[0150] The compounds of Formula (I) are synthesized according to the
procedures set forth in
co-owned and co-pending applications USSN 11/964,461 and PCT/US2007/088978.
One of
skill in the art can readily synthesize compounds of Formula (I) as taught in
these patent
applications.
[0151] In another aspect, provided herein are methods of treating an
inflammatory
gastrointestinal disease or a gastrointestinal condition involving
malabsorption of nutrients
and/or fluids in a patient in need thereof, the methods comprising
administering to the patient a
therapeutically effective amount of a compound of Formula (I):
37

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X2RY
R1 \A U (R7)p
(R2 )q
(I)
wherein,
D is selected from the group consisting of 0, S, and Nle,
X, Y, and Z are independently selected from the group consisting of 0, N,
NIR8, S, and CR3
and at least one of X, Y, and Z is 0, N, Nle, or S;
J, K, T, and U are each independently selected from the group consisting of C,
CH, and N;
the subscript p is an integer of from 0 to 4;
the subscript q is an integer of from 0 to 4;
R' is a member selected from the group consisting of H, Ci_ioalkyl,
Ci_iosubstituted alkyl, C3-
7cyc1oa1ky1, C2_10alkenyl, C2.10alkynyl, XlCORa,-Xl-0O21e,
-Xl-CONRaltb, -S021e, a 4- to 7-membered heterocyclo group, aryl and a 5- to
10-
membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo
group,
aryl group and heteroaryl group is optionally substituted with from 1 to 4
substituents
independently selected from halo, Ci_ioalkyl,
Ci_iosubstituted alkyl, C3_7cycloalkyl, C2.10 alkenyl, C2.10alkynyl, aryl,
heteroaryl,
-CN, -NRaCORb, -NRaCONRaltb, -NO2, -01e, -NRaRb, -CORa, -CO2Ra,
-CONRaRb, -S(0)Ra, -NRaS(0)2Rb, and ¨SO2NRaRb, or optionally Ra and Rb are
combined to form a 4-, 5- or 6-membered ring, and Xl is selected from the
group
consisting of a bond, C2.6alkene, C2_6alkyne, -C(0)-, and -C(0)-(CH2)1.4-,
wherein the
aliphatic portions of Xl are optionally substituted with one to three members
selected
from halogen, Ci.4alkyl, C1.4substituted alkyl and Ci.4haloalkyl;
each R2 is a member independently selected from the group consisting of
halogen,
C1-5 alkyl, C1.5substituted alkyl, C3_7cycloalkyl, -CORa, -CO2Ra, -CONRaRb,
-0Ra, -NRaRb, -NRaCORb, -SORaRb, -SO2Ra and -SO2NRaRb, and wherein when the
subscript q is 2 and R2 is alkyl or substituted alkyl, the two R2 members can
optionally
cyclize to form a ring;
R3 is a member selected from the group consisting of hydrogen, halogen,
Ci.4alkyl, and C1.
4ha1oa1ky1;
each R7 is independently selected from the group consisting of halo,
Ci_loalkyl,
38

CA 03032432 2019-01-29
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Ci_io substituted alkyl, C3_7cycloalkyl, C2-ioalkenyl, C2.10alkynyl, -CN, -
NO2,
-0Ra, -NRaRb, -CORa, -CO2Ra, -CONRaRb, -NRaCORb, -NRaCO2Rb,
-NRaCONRaRb, -S(0)Ra, -NRaS(0)mRb, -SO2NRaRb, a 4- to 7-membered heterocyclo
group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said
heterocyclo
groups, said aryl and heteroaryl groups are optionally substituted with from
one to four
sub stituents independently selected from halo, oxo, C1-4 alkyl, C1-4
haloalkyl, C3-7
cycloalkyl, -CN, -NO2, -0Ra, -NRaRb, -CORa,
-0O2Ra, -CONRaRb, -NRaCORb, 4RaCO2Rb, -NRaCONRaRb, -S(0)Ra,
-NRaSO2Rb, and -SO2NRaRb and wherein the subscript m is an integer of from 0
to 2, or
optionally Ra and Rb are combined to form a 4-, 5- or 6-membered ring;
R8 is a member independently selected from the group consisting of hydrogen,
Ci_4alkyl, and Ci4haloalkyl;
and each Ra and Rb is independently selected from the group consisting of
hydrogen, C1-10
alkyl, Cmohaloalkyl, C3.10cycloalkyl, heterocyclyl, C2.10alkenyl,
C2.10alkynyl, aryl, 5- to 6-membered heteroaryl and ary1C1.4alkyl; and wherein
the
aliphatic portions of each of said Ra and Rb is optionally substituted with
from one to
three members selected from the group consisting of halo, -OR", -000Rn,
-0C(0)N(102, -S(0)1e, -S(0)2R, -S(0)2N(R)2, -NIVS(0)21e,
-C(0)N(102, -C(0)1e, -NIVC(0)1e, -NRT(0)N(Rn)2, -0O21e, -NIVCO2Rn,
-CN, -NO2, -N(Rn)2 and -NleS(0)2N(102, wherein each le is independently
hydrogen
or an unsubstituted C1.6 alkyl;
and wherein the aryl and heteroaryl portions are optionally substituted with
from one to three
members selected from halogen, -ORm, -0C(0)N(Rm)2, -SRm, -S(0)Rm,
-S(0)2Rm, -S(0)2N(Rm)2, -NRmS(0)2Rm, -C(0)N(Rm)2, -C(0)Rm, -NRmC(0)Rm,
-NRmC(0)N(Rm)2, -CO2Rm, -NRmCO2Rm, -CN, -NO2, -N(Rm)2 and
-NRmS(0)2N(Rm)2, wherein each Rm is independently hydrogen or an unsubstituted
Ci.6
alkyl; or a pharmaceutically acceptable salt or ester thereof; and wherein the
molecular
weight of said compound is less than 1200.
[0152] In some embodiments, the compound of Formula (I) is selected from the
group
consisting of the compounds of examples 1-210. In further embodiments, the
compound of
Formula (I) is selected from the group consisting of the compounds of examples
52, 76, 77, 95,
148, 162, 170, 171, 182, 184, 185, and 195. In still further embodiments, the
compound of
39

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Formula (I) is 5 -Ethy1-2- { 4- [4-(4-tetrazol- 1 -yl-phenoxymethyl)-thi azol-
2-yl] -pip eridin- 1 -yl }-
pyrimidine or a pharmaceutically acceptable salt thereof. The structure of the
compound is
shown below.
Ssk
N/Th
N N 0 110
i/C:N NN
[0153] In another aspect, provided herein are methods of treating an
inflammatory
gastrointestinal disease or a gastrointestinal condition involving
malabsorption of nutrients
and/or fluids in a patient in need thereof, the methods comprising
administering to the patient a
therapeutically effective amount of a DPP IV inhibitor and a therapeutically
effective amount of
a compound of Formula (I):
X¨Y
R1 NA U (R7)p
(R2 )q
(I)
wherein,
D is selected from the group consisting of 0, S, and Nle,
X, Y, and Z are independently selected from the group consisting of 0, N,
NIR8, S, and CR3
and at least one of X, Y, and Z is 0, N, Nle, or S;
J, K, T, and U are each independently selected from the group consisting of C,
CH, and N;
the subscript p is an integer of from 0 to 4;
the subscript q is an integer of from 0 to 4;
R' is a member selected from the group consisting of H, Ci_ioalkyl,
Ci_iosubstituted alkyl, C3-
7cyc1oa1ky1, C2.10alkenyl, C2.10alkynyl, -Xl-CORa, -Xl-CO2Ra,
-Xi_c 0NRa-Kb, _
SO2Ra, a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-
membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo
group,
aryl group and heteroaryl group is optionally substituted with from 1 to 4
substituents
independently selected from halo, Ci_ioalkyl,
Ci_iosubstituted alkyl, C3_7cycloalkyl, C2.10 alkenyl, C2.10alkynyl, aryl,
heteroaryl,

CA 03032432 2019-01-29
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-CN, -NRaCORb, -NRaCONRaltb, -NO2, -01e, -NRaltb, -CORa, -CO2Ra,
-CONRaRb, -S(0)Ra, -NRaS(0)2Rb, and -SO2NRaRb, or optionally Ra and Rb are
combined to form a 4-, 5- or 6-membered ring, and X' is selected from the
group
consisting of a bond, C2_6alkene, C2_6alkyne, -C(0)-, and -C(0)-(CH2)1.4-,
wherein the
aliphatic portions of Xl are optionally substituted with one to three members
selected
from halogen, Ci_4alkyl, C1_4substituted alkyl and Ci_4haloalkyl;
each R2 is a member independently selected from the group consisting of
halogen,
C1-5 alkyl, C1-5substituted alkyl, C3-7cycloalkyl, -CORa, -CO2Ra, -CONRaRb,
-0Ra, -NRaRb, -NRaCORb, -SORaRb, -SO2Ra and -SO2NRaRb, and wherein when the
subscript q is 2 and R2 is alkyl or substituted alkyl, the two R2 members can
optionally
cyclize to form a ring;
R3 is a member selected from the group consisting of hydrogen, halogen,
Ci_4alkyl, and Ci.
4ha1oa1ky1;
each R7 is independently selected from the group consisting of halo,
Ci_loalkyl,
Ci_io substituted alkyl, C3.7cycloalkyl, C2.10alkenyl, C2.10alkynyl, -CN, -
NO2,
-0Ra, -NRaRb, -CORa, -CO2Ra, -CONRaRb, -NRaCORb, -NRaCO2Rb,
-NRaCONRaRb, -NRaS(0)Rb, -SO2NRaRb, a 4- to 7-membered heterocyclo
group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said
heterocyclo
groups, said aryl and heteroaryl groups are optionally substituted with from
one to four
sub stituents independently selected from halo, oxo, C1-4 alkyl, C1-4
haloalkyl, C3-7
cycloalkyl, -CN, -NO2, -0Ra, -NRaRb, -CORa,
-0O2Ra, -CONRaRb, -NRaCORb, 4RaCO2Rb, -NRaCONRaRb,
-NRaSO2Rb, and -SO2NRaRb and wherein the subscript m is an integer of from 0
to 2, or
optionally Ra and Rb are combined to form a 4-, 5- or 6-membered ring;
R8 is a member independently selected from the group consisting of hydrogen,
Ci_4alkyl, and Ci_4haloalkyl;
and each Ra and Rb is independently selected from the group consisting of
hydrogen, C1-10
alkyl, Cmohaloalkyl, C3.10cycloalkyl, heterocyclyl, C2.10alkenyl,
C2.10alkynyl, aryl, 5- to 6-membered heteroaryl and ary1C1.4alkyl; and wherein
the
aliphatic portions of each of said Ra and Rb is optionally substituted with
from one to
three members selected from the group consisting of halo, -0r,
-0C(0)N(102, -S(0)1e, -S(0)21e, -S(0)2N(102, -NleS(0)21e,
41

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-C(0)N(102, -C(0)1e, -NIVC(0)1e, -NRI1C(0)N(R11)2, -0O21e, -NIVCO2R11,
-CN, -NO2, -N(102 and -NleS(0)2N(102, wherein each le is independently
hydrogen
or an unsubstituted C1-6 alkyl;
and wherein the aryl and heteroaryl portions are optionally substituted with
from one to three
members selected from halogen, -OR', -0C(0)N(Rm)2, -S(0)Rm,
-S(0)2Rin, -S(0)2N(Rm)2, -NRInS(0)2Rin, -C(0)N(Rm)2, -C(0)Rm, -Nlet (0)Rm,
-NRI'C(0)N(Rin)2, -CO2Rm, -NRITO2Rin, -CN, -NO2, -N(Rm)2 and
-NRInS(0)2N(Rm)2, wherein each Itm is independently hydrogen or an
unsubstituted C1.6
alkyl; or a pharmaceutically acceptable salt or ester thereof; and wherein the
molecular
weight of said compound is less than 1200.
[0154] In some embodiments, the compound of Formula (I) is selected from the
group
consisting of the compounds of examples 1-210. In further embodiments, the
compound of
Formula (I) is selected from the group consisting of the compounds of examples
52, 76, 77, 95,
148, 162, 170, 171, 182, 184, 185, and 195. In still further embodiments, the
compound of
Formula (I) is 5-Ethy1-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidin-l-y1}-
pyrimidine or a pharmaceutically acceptable salt thereof. The structure of the
compound is
shown below.
SITh
N N 0
r(l
N
- N
[0155] Illustrative DPP IV inhibitors include, but are not limited to,
sitagliptin (Merck),
vildagliptin (Novartis), BMS-477118 (saxagliptin) (Bristol-Myers Squibb), BI-
1356 (linagliptin)
(Boehringer Ingelheim), R1438 (aminomethylpyridine) (Roche), NVP DPP728
(Novartis),
P5N9301 (Prosidion), P32/98 (isoleucine thiozolidide) (Probiodrug), G5K823093C

(denagliptin) (Glaxo Smithkline), SYR-322 (Alogliptin) (Takeda), NN-7201
(NovoNordisk),
ALS2-0426 (Alantos), LC15-0444 (gemigliptin) (LG Life Sciences), SK-0403
(anagliptin)
(Kowa), teneligliptin (Mitsubishi Tanabe), trelagliptin (Takeda), dutogliptin
(Phenomix), and
omarigliptin (Merck). (see, e.g., Green BD, Flatt PR, Bailey CJ, Dipeptidyl
peptidase D3 (DPP
IV) inhibitors: a newly emerging drug class for the treatment of Type II
diabetes, Diabetes Vasc
Dis Res 2006, 3:159-165) In some embodiments, the DPP IV inhibitor is selected
from the
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group consisting of sitagliptin, vildagliptin, saxagliptin, linagliptin,
gemigliptin, anagliptin,
teneligliptin, trelagliptin, omarigliptin, and alogliptin. In still further
embodiments, the DPP IV
inhibitor is sitagliptin or vildagliptin.
[0156] The compound of Formula (I) and DPP IV inhibitor are administered in a
single dosage
or in separate dosages. The single dosage is administered once a day or
multiple times a day.
When the compound of Formula (I) and DPP IV inhibitor are administered in
separate dosages,
the dosages are administered once a day or multiple times a day.
[0157] In some embodiments, when the compound of Formula (I) and the DPP IV
inhibitor are
administered in a single dosage, the compound of Formula (I) and DPP IV
inhibitor are
formulated as a medicament into a single pill, single tablet, or a single
capsule. When the
compound of Formula (I) and DPP IV inhibitor are administered in separate
dosages, the
compound of Formula (I) is formulated as a medicament into a pill, tablet or
capsule and the
DPP IV inhibitor is formulated into a separate pill or capsule.
[0158] When the compound of Formula (I) and DPP IV inhibitor are administered
in separate
dosages, the compound of Formula (I) can be administered first and the DPP IV
inhibitor can be
administered next, following administration of the compound of Formula (I).
Alternatively, the
DPP IV inhibitor can be administered first and the compound of Formula (I) can
be administered
next, following administration of the DPP IV inhibitor. The time between the
sequential first
administration and the second administration can be varied by a skilled
practitioner. In some
embodiments, the first administration (a compound of Formula (I) or DPP IV
inhibitor), is
followed immediately by the second administration (a compound of Formula (I)
or DPP IV
inhibitor). In some embodiments, the second administration is within 2
minutes, 5 minutes, 10
minutes, 15 minutes, 30 minutes, or 60 minutes, 1 hour, 2 hours, 3 hours, 4
hours, 5 hours, 6
hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours following
the first
administration. Yet other embodiment provide for the administration to a
patient a compound
for Formula (I) and/or DPP IV inhibitor in the morning followed by
administration to the
previously treated patient a compound of Formula (I) and/or DPP IV inhibitor
in the evening.
[0159] In some embodiments, the method further comprises administering a
therapeutically
effective amount of metformin. Administration of metformin may be sequentially
or
concurrently performed with the administration of the GPR119 agonist (e.g.,
the compound of
Formula (I)) or the combination of GPR119 agonist and DPP IV inhibitor.
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[0160] The compound of Formula (I), DPP IV inhibitor, and metformin are
administered in a
single dosage or in separate dosages. The single dosage is administered once a
day or multiple
times a day. When the compound of Formula (I), DPP IV inhibitor, and metformin
are
administered in separate dosages, the dosages are administered once a day or
multiple times a
day.
[0161] In some embodiments, when the compound of Formula (I), DPP IV
inhibitor, and
metformin are administered in a single dosage, the compound of Formula (I),
DPP IV inhibitor,
and metformin are formulated as a medicament into a single pill, single
tablet, or a single
capsule. In some embodiments, when the compound of Formula ((I), DPP IV
inhibitor, and
metformin are administered in separate dosages, the compound of Formula (I) is
formulated as a
medicament into a pill, tablet or capsule, the DPP IV inhibitor is formulated
into a separate pill
or capsule, and metformin is formulated into a separate pill or capsule.
[0162] The time between the sequential first administration of the compound of
Formula (I)
and the second administration of the compound of Formula (I), and the timing
of the
administration of the DPP IV inhibitor and metformin, can be varied by a
skilled practitioner. In
some embodiments, the first administration (a compound of Formula (I), DPP IV
inhibitor, or
metformin, or any combination thereof), is followed immediately by the second
administration
(a compound of Formula (I), DPP IV inhibitor, or metformin, or any combination
thereof). In
another embodiment, the second administration is within 2 minutes, 5 minutes,
10 minutes, 15
minutes, 30 minutes, or 60 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5
hours, 6 hours, 7 hours,
8 hours, 9 hours, 10 hours, 11 hours, or 12 hours following the first
administration. Yet other
embodiments provide for the administration to a patient a compound for Formula
(I), DPP IV
inhibitor, or metformin, or any combination thereof, in the morning followed
by administration
to the previously treated patient a compound of Formula (I), DPP IV inhibitor,
or metformin, or
any combination thereof, in the evening.
[0163] In another aspect, provided herein are methods of improving the
intestinal wall health
and integrity of a patient in need thereof, the method comprising
administering to the patient a
therapeutically effective amount of a compound of Formula (I).
[0164] In another aspect, provided herein are methods of improving the
intestinal wall health
and integrity of a patient in need thereof, the method comprising
administering to the patient a
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therapeutically effective amount of a compound of Formula (I) and a
therapeutically effective
amount of a DPP IV inhibitor.
[0165] In another aspect, provided herein are methods of improving the
intestinal wall health
and integrity of a patient in need thereof, the method comprising
administering to the patient a
therapeutically effective amount of a compound of Formula (I), a
therapeutically effective
amount of a DPP IV inhibitor, and a therapeutically effective amount of
metformin.
[0166] In another aspect, provided herein are methods of maintaining the
intestinal wall health
and integrity of a patient in need thereof, the method comprising
administering to the patient a
therapeutically effective amount of a compound of Formula (I).
[0167] In another aspect, provided herein are methods of maintaining the
intestinal wall health
and integrity of a patient in need thereof, the method comprising
administering to the patient a
therapeutically effective amount of a compound of Formula (I) and a
therapeutically effective
amount of a DPP IV inhibitor.
[0168] In another aspect, provided herein are methods of maintaining the
intestinal wall health
and integrity of a patient in need thereof, the method comprising
administering to the patient a
therapeutically effective amount of a compound of Formula (I), a
therapeutically effective
amount of a DPP IV inhibitor, and a therapeutically effective amount of
metformin.
[0169] In another aspect disclosed herein, a therapeutically effective amount
of a compound of
Formula (I) and optionally, a therapeutically effective amount of DPP IV
inhibitor or a
therapeutically effective amount of DPP IV inhibitor and metformin, can be
used for the
preparation of one or more pharmaceutical compositions useful for treating an
inflammatory
gastrointestinal disease or a gastrointestinal condition involving
malabsorption of nutrients
and/or fluids.
[0170] The compositions disclosed herein may include compounds of Formula (I),
and
optionally, DPP IV inhibitors or DPP IV inhibitors and metformin,
pharmaceutically acceptable
salts thereof, or a hydrolysable precursor thereof. In general, the compound
is mixed with
suitable carriers or excipient(s) in a therapeutically effective amount. By a
"therapeutically
effective dose", "therapeutically effective amount", or, interchangeably,
"pharmacologically
acceptable dose" or "pharmacologically acceptable amount", it is meant that a
sufficient amount
of the compound disclosed herein and a pharmaceutically acceptable carrier
will be present in

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order to achieve a desired result, e.g., alleviating a symptom or complication
of a disease or
condition.
[0171] The compounds of Formula (I), optional DPP IV inhibitors and optional
metformin that
are used in the methods disclosed herein can be incorporated into a variety of
formulations for
therapeutic administration. More particularly, the compounds of Formula (I),
optional DPP IV
inhibitors and optional metformin can be formulated into pharmaceutical
compositions by
combination with appropriate, pharmaceutically acceptable carriers or
diluents, and can be
formulated into preparations in solid, semi-solid, liquid or gaseous forms,
such as tablets,
capsules, pills, powders, granules, dragees, gels, slurries, ointments,
solutions, suppositories,
injections, inhalants and aerosols. The compounds of Formula (I), optional DPP
IV inhibitors
and optional metformin can be formulated into a single composition containing
a compound of
Formula (I), optional DPP IV inhibitor and optional metformin. Alternatively,
the compound of
Formula (I), optional DPP IV inhibitor and optional metformin can be
formulated into separate
pharmaceutical formulations and manufactured into a single pill, tablet or
capsule that physically
separates the compound of Formula (I), optional DPP IV inhibitor and optional
metformin. The
administration of the compounds can be achieved in various ways, including
oral, buccal, rectal,
parenteral, intraperitoneal, intradermal, transdermal, and/or intratracheal
administration.
Moreover, the compound can be administered in a local rather than systemic
manner, in a depot
or sustained release formulation. In addition, the compounds can be
administered in a liposome.
[0172] DPP IV inhibitors are commercially available. In particular,
sitagliptin is an approved
pharmaceutical marketed as JANUVIATm, vildagliptin is an approved
pharmaceutical marketed
as GALVUSTm, and linagliptin is an approved pharmaceutical marketed as
TRADJENTA .
[0173] The compounds of Formula (I), optional DPP IV inhibitors and optional
metformin can
be formulated with common excipients, diluents or carriers, and compressed
into tablets, or
formulated as elixirs or solutions for convenient oral administration, or
administered by the
intramuscular or intravenous routes. The compounds can be administered
transdermally, and
can be formulated as sustained release dosage forms and the like.
[0174] Suitable formulations for use in the methods and compositions disclosed
herein are
found in Remington's Pharmaceutical Sciences (Mack Publishing Company (1985)
Philadelphia,
PA, 17th ed.), which is incorporated herein by reference. Moreover, for a
brief review of
methods for drug delivery, see, Langer, Science (1990) 249:1527-1533, which is
incorporated
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herein by reference. The pharmaceutical compositions described herein can be
manufactured in
a manner that is known to those of skill in the art, i.e., by means of
conventional mixing,
dissolving, granulating, dragee-making, levigating, emulsifying,
encapsulating, entrapping or
lyophilizing processes. The following methods and excipients are merely
exemplary and are in
no way limiting.
[0175] For injection, the compound of Formula (I), optional DPP IV inhibitor
and optional
metformin can be formulated into preparations by dissolving, suspending or
emulsifying them in
an aqueous or nonaqueous solvent, such as vegetable or other similar oils,
synthetic aliphatic
acid glycerides, esters of higher aliphatic acids or propylene glycol; and if
desired, with
conventional additives such as solubilizers, isotonic agents, suspending
agents, emulsifying
agents, stabilizers and preservatives. Preferably, the compounds disclosed
herein can be
formulated in aqueous solutions, preferably in physiologically compatible
buffers such as
Hanks' solution, Ringer's solution, or physiological saline buffer. For
transmucosal
administration, penetrants appropriate to the barrier to be permeated are used
in the formulation.
Such penetrants are generally known in the art.
[0176] For oral administration, the compounds of Formula (I), optional DPP IV
inhibitors and
optional metformin can be formulated readily by combining with
pharmaceutically acceptable
carriers that are well known in the art. Such carriers enable the compounds to
be formulated as
tablets, pills, dragees, capsules, emulsions, lipophilic and hydrophilic
suspensions, liquids, gels,
syrups, slurries, suspensions and the like, for oral ingestion by a patient to
be treated.
Pharmaceutical preparations for oral use can be obtained by mixing the
compounds with a solid
excipient, optionally grinding a resulting mixture, and processing the mixture
of granules, after
adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
Suitable excipients are,
in particular, fillers such as sugars, including lactose, sucrose, mannitol,
or sorbitol; cellulose
preparations such as, for example, maize starch, wheat starch, rice starch,
potato starch, gelatin,
gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium
carboxymethylcellulose, and/or polyvinylpyrrolidone. If desired,
disintegrating agents can be
added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid
or a salt thereof such
as sodium alginate.
[0177] Dragee cores are provided with suitable coatings. For this purpose,
concentrated sugar
solutions can be used, which can optionally contain gum arabic, talc,
polyvinyl pyrrolidone,
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carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions,
and suitable
organic solvents or solvent mixtures. Dyestuffs or pigments can be added to
the tablets or
dragee coatings for identification or to characterize different combinations
of active compound
doses.
[0178] Pharmaceutical preparations that can be used orally include push-fit
capsules made of
gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer,
such as glycerol or
sorbitol. The push-fit capsules can contain the active ingredients in
admixture with filler such as
lactose, binders such as starches, and/or lubricants such as talc or magnesium
stearate and,
optionally, stabilizers. In soft capsules, the active compounds can be
dissolved or suspended in
suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene
glycols. In addition,
stabilizers can be added. All formulations for oral administration should be
in dosages suitable
for such administration.
[0179] For buccal administration, the compositions can take the form of
tablets or lozenges
formulated in conventional manner.
[0180] For administration by inhalation, the compounds for use in the methods
and
compositions disclosed herein are conveniently delivered in the form of an
aerosol spray
presentation from pressurized packs or a nebulizer, with the use of a suitable
propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane,
carbon dioxide or
other suitable gas, or from propellant-free, dry-powder inhalers. In the case
of a pressurized
aerosol the dosage unit can be determined by providing a valve to deliver a
metered amount.
Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator
can be formulated
containing a powder mix of the compound and a suitable powder base such as
lactose or starch.
[0181] The compounds can be formulated for parenteral administration by
injection, e.g., by
bolus injection or continuous infusion. Formulations for injection can be
presented in unit
dosage form, e.g., in ampoules or in multidose containers, with an added
preservative. The
compositions can take such forms as suspensions, solutions or emulsions in
oily or aqueous
vehicles, and can contain formulator agents such as suspending, stabilizing
and/or dispersing
agents.
[0182] Pharmaceutical formulations for parenteral administration include
aqueous solutions of
the active compounds in water-soluble form. Additionally, suspensions of the
active compounds
can be prepared as appropriate oily injection suspensions. Suitable lipophilic
solvents or
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vehicles include fatty oils such as sesame oil, or synthetic fatty acid
esters, such as ethyl oleate
or triglycerides, or liposomes. Aqueous injection suspensions can contain
substances that
increase the viscosity of the suspension, such as sodium carboxymethyl
cellulose, sorbitol, or
dextran. Optionally, the suspension can also contain suitable stabilizers or
agents that increase
the solubility of the compounds to allow for the preparation of highly
concentrated solutions.
Alternatively, the active ingredient can be in powder form for constitution
with a suitable
vehicle, e.g., sterile pyrogen-free water, before use.
[0183] The compounds can also be formulated in rectal compositions such as
suppositories or
retention enemas, e.g., containing conventional suppository bases such as
cocoa butter,
carbowaxes, polyethylene glycols or other glycerides, all of which melt at
body temperature, yet
are solidified at room temperature.
[0184] In addition to the formulations described previously, the compounds can
also be
formulated as a depot preparation. Such long acting formulations can be
administered by
implantation (for example subcutaneously or intramuscularly) or by
intramuscular injection.
Thus, for example, the compounds can be formulated with suitable polymeric or
hydrophobic
materials (for example as an emulsion in an acceptable oil) or ion exchange
resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble salt.
[0185] Alternatively, other delivery systems for hydrophobic pharmaceutical
compounds can
be employed. Liposomes and emulsions are well known examples of delivery
vehicles or
carriers for hydrophobic drugs. In a presently preferred embodiment, long-
circulating, i.e.,
stealth liposomes can be employed. Such liposomes are generally described in
Woodle, et al.,
U.S. Patent No. 5,013,556. The compounds disclosed herein can also be
administered by
controlled release means and/or delivery devices such as those described in
U.S. Patent Nos.
3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719.
[0186] Certain organic solvents such as dimethylsulfoxide ("DMSO") also can be
employed,
although usually at the cost of greater toxicity. Additionally, the compounds
can be delivered
using a sustained-release system, such as semipermeable matrices of solid
hydrophobic
polymers containing the therapeutic agent. Various types of sustained-release
materials have
been established and are well known by those skilled in the art. Sustained-
release capsules can,
depending on their chemical nature, release the compounds for a few hours up
to over 100 days.
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[0187] The pharmaceutical compositions also can comprise suitable solid or gel
phase carriers
or excipients. Examples of such carriers or excipients include but are not
limited to calcium
carbonate, calcium phosphate, various sugars, starches, cellulose derivatives,
gelatin, and
polymers such as polyethylene glycols.
[0188] Pharmaceutical compositions suitable for use in the methods disclosed
herein include
compositions wherein the active ingredients are contained in a therapeutically
effective amount.
The amount of composition administered will, of course, be dependent on the
subject being
treated, on the subject's weight, the severity of the affliction, the manner
of administration and
the judgment of the prescribing physician. Determination of an effective
amount is well within
the capability of those skilled in the art, especially in light of the
detailed disclosure provided
herein.
[0189] For any compound used in the method disclosed herein, a therapeutically
effective dose
can be estimated initially from cell culture assays, animal models, or
microdosing of human
subjects.
[0190] Moreover, toxicity and therapeutic efficacy of the compounds described
herein can be
determined by standard pharmaceutical procedures in cell cultures or
experimental animals, e.g.,
by determining the LD50, (the dose lethal to 50% of the population) and the
ED50 (the dose
therapeutically effective in 50% of the population). The dose ratio between
toxic and
therapeutic effect is the therapeutic index and can be expressed as the ratio
between LD50 and
ED50. Compounds that exhibit high therapeutic indices are preferred. The data
obtained from
these cell culture assays and animal studies can be used in formulating a
dosage range that is not
toxic for use in humans. The dosage of such compounds lies preferably within a
range of
circulating concentrations that include the ED50 with little or no toxicity.
The dosage can vary
within this range depending upon the dosage form employed and the route of
administration
utilized. The exact formulation, route of administration and dosage can be
chosen by the
individual physician in view of the patient's condition. (see, e.g., Fingl, et
al., 1975 In: The
Pharmacological Basis of Therapeutics, Ch. 1).
[0191] The amount of active compound that can be combined with a carrier
material to
produce a single dosage form will vary depending upon the disease or condition
treated, the
mammalian species, and the particular mode of administration. However, as a
general guide,
suitable unit doses for the compounds disclosed herein can, for example,
preferably contain

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between 0.1 mg to about 1000 mg of the active compound. A preferred unit dose
is between 1
mg to about 500 mg. A more preferred unit dose is between 1 mg to about 300mg.
Even more
preferred unit dose is between 1 mg to about 100 mg. Such unit doses can be
administered more
than once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or
2 times per day, so
that the total dosage for a 70 kg adult is in the range of 0.001 to about 15
mg per kg weight of
subject per administration. A preferred dosage is 0.01 to about 1.5 mg per kg
weight of subject
per administration, and such therapy can extend for a number of weeks or
months, and in some
cases, years. It will be understood, however, that the specific dose level for
any particular
patient will depend on a variety of factors including the activity of the
specific compound
employed; the age, body weight, general health, sex and diet of the individual
being treated; the
time and route of administration; the rate of excretion; other drugs that have
previously been
administered; and the severity of the particular disease or condition
undergoing therapy, as is
well understood by those of skill in the area.
[0192] A typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to
about 300 mg
taken once a day, or, multiple times per day, or one time-release capsule or
tablet taken once a
day and containing a proportionally higher content of active ingredient. The
time-release effect
can be obtained by capsule materials that dissolve at different pH values, by
capsules that release
slowly by osmotic pressure, or by any other known means of controlled release.
[0193] It can be necessary to use dosages outside these ranges in some cases
as will be
apparent to those skilled in the art. Further, it is noted that the clinician
or treating physician
will know how and when to start, interrupt, adjust, or terminate therapy in
conjunction with
individual patient response.
[0194] The dosing of a compound of Formula (I), optional DPP IV inhibitor and
optional
metformin can be dosed at the same time, within several minutes, or separated
by hours. By
way of example, a compound of Formula (I), optional DPP IV inhibitor and
optional metformin
can be dosed together in the morning, with no further dosing for the remainder
of the day.
Alternatively, in the morning, a compound of Formula (I), optional DPP IV
inhibitor and
optional metformin is dosed followed with a second dose of a compound of
Formula (I), a DPP
IV inhibitor, or metformin, or any combination thereof, in the evening or
after a meal.
[0195] It can be necessary to administer dosages of the compound of Formula
(I) and optional
DPP IV inhibitor and optional metformin once a day or more than once a day, or
before or after
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a meal, as will be apparent to those skilled in the art. Further, it is noted
that the clinician or
treating physician will know how and when to start, interrupt, adjust, or
terminate therapy in
conjunction with individual patient response.
[0196] In addition, in another aspect, provided herein are kits with unit
doses of the
compounds of Formula (I), DPP IV inhibitor, or metformin, or any combination
thereof, either
in oral or injectable doses. In addition to the containers containing the unit
doses will be an
informational package insert describing the use and attendant benefits of the
drugs in treating
inflammatory gastrointestinal diseases or gastrointestinal conditions
involving malabsorption of
nutrients and/or fluids. Preferred compounds and unit doses are those
described herein above.
[0197] For the compositions, methods and kits provided above, one of skill in
the art will
understand that preferred compounds for use in each are those compounds that
are noted as
preferred above. Still further preferred compounds for the compositions,
methods and kits are
those compounds provided in the non-limiting Examples below.
EXAMPLES
[0198] General Methods: All operations involving moisture and/or oxygen
sensitive
materials were conducted under an atmosphere of dry nitrogen in pre-dried
glassware. Unless
noted otherwise, materials were obtained from commercially available sources
and used without
further purification.
[0199] Flash chromatography was performed on E. Merck silica gel 60 (240-400
mesh)
according to the protocol of Still, Kahn, and Mitra (J. Org. Chem. (1978) 43,
2923). Thin layer
chromatography was performed using precoated plates purchased from E. Merck
(silica gel 60
PF254, 0.25 mm) and spots were visualized with ultraviolet light followed by
an appropriate
staining reagent.
[0200] Nuclear magnetic resonance ("NMR") spectra were recorded on a Varian
Inova-400
resonance spectrometer. 11-1NMR chemical shifts are given in parts per million
(6) downfield
from tetramethylsilane ("TMS") using TMS or the residual solvent signal
(CHC13=6 7.24,
DMSO = 6 2.50) as internal standard. 1HNMR information is tabulated in the
following format:
number of protons, multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet),
coupling contant(s) (J) in Hertz, and, in selected cases, position assignment.
The prefix app is
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occasionally applied in cases where the true signal multiplicity was
unresolved and br indicates
the signal in question was broadened.
[0201] Preparation of Intermediate 1: 4-(4-Chloromethyl-thiazol-2-y1)-
piperidine-1-
carboxylic acid tert-butyl ester
CI
To a solution of 4-thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester
(4.9 g, 20
mmol) in acetone (80 mL) was added 1,3-dichloroacetone (3.3 g, 26 mmol), MgSO4
(3.6 g, 30
mmol) and MgCO3 (1.68 g, 20 mmol). The mixture was heated under reflux
overnight, cooled
and filtered through celite. The solvent was removed in vacuo and the residue
was redissolved
with Et0Ac (150 mL). The resulting solution was washed successively with 5%
NaHS03,
saturated NaHCO3, and brine. After drying (Na2SO4), the solvent was removed to
afford the
desired product. 1H NMR (CDC13): 6 7.20 (1H, s), 4.67 (2H, s), 4.20 (2H, br),
3.16 (1H, m),
2.87 (2H, m), 2.09 (2H, m), 1.72 (2H, m), 1.47 (9H, s).
[0202] Preparation of Intermediate 2: 244-(4-Chloromethyl-thiazol-2-y1)-
piperidin-1-y1]-5-
ethyl-pyrimidine
s-L/CI
Et N
[0203] Intermediate 2 was prepared in a manner analogous to Intermediate 1
above.
[0204] 11-1NMR (DMSO-d6): 6 8.45 (2H, d), 7.62 (1H, s), 4.79 (2H, s), 4.61
(2H, m), 3.41
(1H, m), 3.24 (2H, m), 2.52 (2H, q), 2.15 (2H, m), 1.66 (2H, m), 1.17 (3H, m).
[0205] Preparation of Intermediate 3: 444-(4-Methanesulfonyl-phenoxymethyl)-
thiazol-2-
y1]-piperidine
53

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N
HN
0 r,
0
[0206] A solution of 444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-A-
piperidine-1-
carboxylic acid tert-butyl ester (615 mg, 1.36 mmol) in methanol (10 mL) was
treated with 10
mL of 4 N HC1 in dioxane. The resulting solution was stirred at room
temperature for 30
minutes. Then all the solvents were removed in vacuo to afford the desired
product as a HC1
salt.
[0207] Preparation of Intermediate 4: 444-(4-Tetrazol-1-yl-phenoxymethyl)-
thiazol-2-y1]-
piperidine
HN
0
N7N
\N=N
[0208] Intermediate 4 was prepared in a manner analogous to Intermediate 3
above.
[0209] 1H Wit (DMSO-d6): 6 9.98 (1H, s), 7.82 (2H, m), 7.63 (1H, s), 7.28 (2H,
m), 5.19
(2H, s), 3.01 (3H, m), 2.54 (3H, m), 1.92 (2H, m), 1.54 (2H, m).
[0210] Preparation of Intermediate 5: 444-(2-Fluoro-4-methanesulfonyl-
phenoxymethyl)-
thiazol-2-y1]-piperidine
HN
0 lip r,
0
[0211] Intermediate 5 was prepared in a manner analogous to Intermediate 3
above.
[0212] Preparation of Intermediate 6: 444-(2-Fluoro-4-tetrazol-1-yl-
phenoxymethyl)-
thiazol-2-y1]-piperidine
54

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Th
HN NN
0 =N7N
\N=N
[0213] Intermediate 6 was prepared in a manner analogous to Intermediate 3
above.
[0214] Preparation of Intermediate 7: 444-(3-Fluoro-4-tetrazol-1-yl-
phenoxymethyl)-
thiazol-2-y1]-piperidine
HN
0
ci
N7N
\N=N1
[0215] Intermediate 7 was prepared in a manner analogous to Intermediate 3
above.
[0216] Preparation of Intermediate 8: 444-(2,6-Difluoro-4-tetrazol-1-yl-
phenoxymethyl)-
thiazol-2-y1]-piperidine
HN
0
N7N
\N=N1
[0217] Intermediate 8 was prepared in a manner analogous to Intermediate 3
above.
[0218] Preparation of Intermediate 9: 444-(4-Pyrrol-1-yl-phenoxymethyl)-
thiazol-2-y1]-
piperidine
HN
0
N7
\ ¨
[0219] Intermediate 9 was prepared in a manner analogous to Intermediate 3
above.
[0220] Preparation of Intermediate 10: (2-Piperidin-4-yl-thiazol-4-ylmethyl)-
(4-tetrazol-1-
yl-pheny1)-amine

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N
HN
HN
I\17N
\N=1\1
[0221] Intermediate 10 was prepared in a manner analogous to Intermediate 3
above.
[0222] Preparation of Intermediate 11: 4-[4-(2-Methy1-4-tetrazol-1-yl-
phenoxymethyl)-
thiazol-2-y1]-piperidine
HN
0
I\17N
\N=I\1
[0223] Intermediate 11 was prepared in a manner analogous to Intermediate 3
above.
[0224] Preparation of Intermediate 12: 444-(2-Isopropyl-5-methyl-4-tetrazol-1-
yl-
phenoxymethyl)-thiazol-2-y1]-piperidine
N 0 11* N
N
H-N
CI
[0225] Intermediate 12 was prepared in a manner analogous to Intermediate 3
above.
[0226] Preparation of Intermediate 13: 444-(2-Chloro-4-tetrazol-1-yl-
phenoxymethyl)-
thiazol-2-y1]-piperidine
N 0 11* N
N
H-N
CI
[0227] Intermediate 13 was prepared in a manner analogous to Intermediate 3
above.
[0228] Preparation of Intermediate 14: 4-(4-Chloromethyl-oxazol-2-y1)-
piperidine-1-
carboxylic acid tert-butyl ester
56

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CI
OyN
>0
[0229] A mixture of 4-(4-Hydroxymethyl-oxazol-2-y1)-piperidine-1-carboxylic
acid tert-butyl
ester (800 mg, 2.84 mmol) (obtained by the reduction of 4-(4-ethoxycarbonyl-
oxazol-2-y1)-
piperidine-l-carboxylic acid tert-butyl ester which was synthesized according
to U.S. Patent
Publication No. 2006/0135501 Al), TsC1 (812 mg, 4.26 mmol) and triethylamine
(1 mL, 752
mg, 7.44 mmol) in dichloromethane (20 mL) was stirred at room temperature for
5 hours. The
resulting solution was washed successively with 5% NaHS03, saturated NaHCO3,
and brine.
After drying (Na2SO4), the solvent was removed to afford the desired product.
11-INIVIR
(CDC13): 6 7.53 (s, 1H), 4.40 (s, 2H), 4.06 (m, 2H), 2.89 (m, 3H), 1.98 (m,
2H), 1.74 (m, 2H),
1.41 (s, 9H).
[0230] Preparation of Intermediate 15: 444-(4-Tetrazol-1-yl-phenoxymethyl)-
oxazol-2-y1]-
piperidine
0 111
N
[0231] Intermediate 15 was prepared in a manner analogous to Intermediate 3
above.
[0232] Preparation of Intermediate 16: 444-(2-Fluoro-4-tetrazol-1-yl-
phenoxymethyl)-
oxazol-2-y1]-piperidine
0
N, N
[0233] Intermediate 16 was prepared in a manner analogous to Intermediate 3
above.
[0234] Preparation of Intermediate 17: 5-(2-Piperidin-4-yl-thiazol-4-
ylmethoxy)-2-tetrazol-
1-yl-pyridine
57

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1-1¨Na4N-3
N N
N
[0235] Intermediate 17 was prepared in a manner analogous to Intermediate 3
above.
[0236] Preparation of Intermediate 18: (6-Fluoro-pyridin-3 -y1)-(2-piperidin-4-
yl-thiazol-4-
ylmethyl)-amine
1-1¨Na4N-3
H ,N
[0237] Intermediate 18 was prepared in a manner analogous to Intermediate 3
above.
[0238] Preparation of Intermediate 19: 4-[4-(2, 6-Difluoro-4-methanesulfonyl-
phenoxymethyl)-thiazol-2-y1]-piperidine
0
S,
HN //
0
[0239] Intermediate 19 was prepared in a manner analogous to Intermediate 3
above.
[0240] Preparation of Intermediate 20: 444-(2-Piperidin-4-yl-thiazol-4-
ylmethoxy)-
pheny1]-morpholine
S,
HN ____________________________
1110
NTh
[0241] Intermediate 20 was prepared in a manner analogous to Intermediate 3
above.
58

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[0242] Preparation of Intermediate 21: 444-(2-Piperidin-4-yl-thiazol-4-
ylmethoxy)-
phenyl]-morpholine
0
fik
N
0
HN
[0243] Intermediate 21 was prepared in a manner analogous to Intermediate 3
above.
[0244] Preparation of Intermediate 22: 4-(4-Chloromethyl-thiazol-2-y1)-3-
methyl-
piperidine-1-carboxylic acid tert-butyl ester
CI
[0245] Intermediate 22 was prepared in a manner analogous to Intermediate 1
above.
[0246] Preparation of Intermediate 23: 3-Methyl-444-(4-tetrazol-1-yl-
phenoxymethyl)-
thiazol-2-y1]-piperidine
0
NZN
µN=N
[0247] Intermediate 23 was prepared in a manner analogous to Intermediate 3
above.
[0248] Preparation of Intermediate 24: 444-(2-Fluoro-4-tetrazol-1-yl-
phenoxymethyl)-
thiazol-2-y1]-3-methyl-piperidine
0 /11
N N
HN
[0249] Intermediate 24 was prepared in a manner analogous to Intermediate 3
above.
59

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[0250] Preparation of Intermediate 25: 444-(4-Methanesulfonyl-benzyloxymethyl)-
thiazol-
2-y1]-piperidine

HN ,0
,S'
0' \
[0251] Intermediate 25 was prepared in a manner analogous to Intermediate 3
above.
Example 1
[0252] 444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid
tert-butyl ester
NN
I
O$
0
0
[0253] A mixture of 4-(4-Chloromethyl-thiazol-2-y1)-piperidine-1-carboxylic
acid tert-butyl
ester (Intermediate 1, 463 mg, 1.46 mmol), 4-methanesulfonyl-phenol (252 mg,
1.46 mmol)
and K2CO3 (404 mg, 2.92 mmol) in acetone (25 mL) was heated under reflux
overnight. After
cooling, the solid was filtered through a pad of celite. The filtrate was
concentrated in vacuo.
The residue was purified on silica gel (Et0Ac-hexanes, 1:1) to afford the
desired product. 11-1
NMR (CDC13): 6 7.88 (2H, d, J = 8.8 Hz), 7.23 (1H, s), 7.12 (2H, d, J= 8.8
Hz), 5.24 (2H, s),
4.21 (2H, br), 3.17 (1H, m), 3.04 (3H, s), 2.88 (2H, m), 2.11 (2H, m), 1.73
(2H, m), 1.47 (9H, s).
[0254] The compounds in Examples 2-19 were synthesized from 4-(4-Chloromethyl-
thiazol-
2-y1)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 1), 244-(4-
Chloromethyl-
thiazol-2-y1)-piperidin-1-y1]-5-ethyl-pyrimidine (Intermediate 2), 4-(4-
Chloromethyl-oxazol-2-
y1)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 14) or with
the corresponding
phenol, thiophenol, amine or aniline in a similar manner to that described in
Example 1. One
skilled in the art of organic synthesis will appreciate that conditions such
as solvent (e.g., DMF,
CH3CN); temperature, base (e.g., NEt3, K2CO3, NaHCO3, Na2CO3, Cs2CO3) and
concentration
can be selected through routine experimentation to optimize yields.
Additionally, alternative
coupling methods can be used that are well known in the art of organic
synthesis.

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Example 2
[0255] 444-(4-Imidazo1-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid tert-
butyl ester
0 OS¨Nk/(3 1\lr
\=N
>r0
[0256] 1H NMR (DMSO-d6): 6 8.12 (1H, s), 7.63 (2H, m), 7.54 (2H, d, J= 9.2
Hz), 7.15 (2H,
d, J = 9.2 Hz), 7.05 (1H, s), 5.15 (2H, s), 3.98 (2H, m), 3.21 (1H, m), 2.87
(2H, m), 2.01 (2H,
m), 1.52 (2H, m), 1.39 (9H, s).
Example 3
[0257] 444-(4-Acetylamino-phenoxymethyl)-thiazol-2-y1]-piperidine-1-carboxylic
acid tert-
butyl ester
NH
o 0 3
[0258] 1EINMR (DMSO-d6): 6 9.77 (1H, s), 7.57 (1H, s), 7.45 (2H, d, J= 9.0
Hz), 6.94 (2H,
d, J = 9.0 Hz), 5.04 (2H, s), 3.98 (2H, m), 3.18 (1H, m), 2.82 (2H, m), 2.02
(2H, m), 1.99 (3H,
s), 1.51 (2H, m), 1.39 (9H, s).
Example 4
[0259] 444-(4-Methoxy-benzenesulfonyloxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic
acid tert-butyl ester
S--\\
0
-6/ lip
OMe
61

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[0260] 111 NMR (CDC13): 6 7.60 (2H, d, J= 9.0 Hz), 7.24 (1H, s), 6.91 (2H, d,
J= 9.0 Hz),
4.50 (2H, s), 4.10 (2H, m), 3.85 (3H, s), 2.99 (1H, m), 2.82 (2H, m), 1.89-
1.92 (2H, m),
1.53-1.57 (2H, m), 1.46 (9H, s).
Example 5
[0261] 444-(441,2,4]Triazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid
tert-butyl ester
N177__jN
N 0
>10
[0262] IIINMR (CDC13): 6 8.47 (1H, s), 8.08 (1H, s), 7.58 (2H, d, J= 9.2 Hz),
7.24 (1H, s),
7.11 (2H, d, J= 9.2 Hz), 5.21 (2H, s), 4.2 (2H, m), 3.18 (1H, m), 2.88 (2H,
m), 2.11 (2H, m),
1.74 (2H, m), 1.47 (9H, s).
Example 6
[0263] 4- {444-(2-0xo-pyrrolidin-1-y1)-phenoxymethy1]-thiazol-2-y1} -
piperidine-1-carboxylic
acid tert-butyl ester
0 1110
0;
[0264] 1H NMR (CDC13): 6 7.50(2H, d), 7.20(1H, s), 6.98 (2H, d), 5.17 (2H, s),
4.20 (2H,
br), 3.81(2H, m), 3.18 (1H, m), 2.88 (2H, m), 2.59 (2H, m), 2.16 (4H, m),
1.73(2H, m), 1.46
(9H, s).
Example 7
[0265] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid tert-
butyl ester
62

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0y,N 0
NrN
>i0 1\1=N
[0266] 1-14 NMR (CDC13): 6 8.94 (1H, s), 7.61 (2H, d), 7.25 (1H, s), 7.19 (2H,
d), 5.21 (2H, s),
4.20 (2H, br), 3.20 (1H, m), 2.90 (2H, m), 2.16 (2H, m), 1.77 (2H, m), 1.49
(9H, s).
Example 8
[0267] 444-(4-Methanesulfonyl-phenylsulfanylmethyl)-thiazol-2-y1]-piperidine-1-
carboxylic
acid tert-butyl ester
0
OyN g,
0'
0
[0268] 1-14 NMR (CDC13): 6 7.7 (2H, d, J= 9.0 Hz), 7.36 (2H, d, J= 9.0 Hz),
7.00 (1H, s), 4.24
(2H, s), 4.3 (2H, m), 3.05 (1H, m), 2.95 (3H, s), 2.78 (2H, m), 1.99 (2H, m),
1.62 (2H, m), 1.38
(9H, s).
Example 9
[0269] 4-{241-(5-Ethyl-pyrimidin-2-y1)-piperidin-4-A-thiazol-4-ylmethoxy}-
benzenesulfonamide
NH
9
0
[0270] 1-14 NMR (DMSO-d6): 6 8.24 (2H, s), 7.73 (2H, d), 7.64 (1H, s), 7.20
(4H, m), 5.18
(2H, s), 4.67 (2H, m), 3.38 (1H, m), 3.01 (2H, m), 2.47 (2H, m), 2.08 (2H, m),
1.62 (2H, m),
1.53 (3H, m).
Example 10
2- {444-(2,6-Dichloro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl] -
piperidin-l-yl -5-ethyl-
pyrimidine
63

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CI
S-kzo
ci
--N 0
[0271] 1HNMR (DMSO-d6): 6 8.23 (2H, s), 7.99 (2H, s), 7.68 (1H, s), 5.20 (2H,
s), 4.64 (2H,
m), 3.31 (3H, s), 3.30 (1H, m), 3.0 (2H, m), 2.40 (2H, m), 1.98 (2H, m), 1.54
(2H, m), 1.15 (3H,
m).
Example 11
[0272] 5-Ethy1-2-{444-(3-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
l-y1}-
pyrimidine
11 N
[0273] 1H NMR (CDC13): 6 9.05 (1H, s), 8.19 (2H, s), 7.55-7.10 (5H, m), 5.24
(2H, s), 4.83
(2H, m), 3.30 (1H, m), 3.04 (2H, m), 2.47 (2H, q, J= 7.6 Hz), 2.21 (2H, m),
1.80 (2H, m), 1.19
(3H, t, J= 7.6 Hz).
Example 12
[0274] 5-Ethy1-2-(4-{444-(5-methyl-tetrazol-1-y1)-phenoxymethyl]-thiazol-2-y1}-
piperidin-1-
y1)-pyrimidine
S
NJJNJ
0 = N
--N
N-=-N
[0275] 1H NMR (CDC13): 6 8.19 (2H, s), 7.38 (2H, d, J= 9.0 Hz), 7.26 (1H, s),
7.17 (2H, d, J
= 9.0 Hz), 5.24 (2H, s), 4.84 (2H, m), 3.31 (1H, m), 3.05 (2H, m), 2.58 (3H,
s), 2.47 (2H, q, J=
7.8 Hz), 2.22 (2H, m), 1.82 (2H, m), 1.20 (3H, t, J= 7.8 Hz).
Example 13
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[0276] 5-Ethy1-2-{444-(3-methy1-4-methylsulfanyl-phenoxymethyl)-thiazol-2-A-
piperidin-1-
y1}-pyrimidine
N 0
N
[0277] 1H NMR (DMSO-d6): 6 8.23 (2H, s), 7.56 (1H, s), 7.16 (1H, m), 6.90 (1H,
m), 6.86
(1H, m), 5.06 (2H, s), 4.67 (2H, m), 3.55 (4H, m), 3.01 (2H, m), 2.48 (3H, s),
2.40 (2H, m), 2.09
(2H, m), 1.57 (2H, m), 1.09 (3H, m).
Example 14
[0278] 5-Ethy1-2-{444-(4-methanesulfony1-3-methyl-phenoxymethyl)-thiazol-2-A-
piperidin-
l-y1}-pyrimidine
rLN 0 0
N
0
[0279] 1H NMR (DMSO-d6): 6 8.13 (2H, s), 7.91 (1H, m), 7.20 (1H, s), 6.85 (2H,
m), 5.14
(2H, s), 4.76 (2H, m), 3.23 (1H, m), 2.98 (3H, s), 2.60 (3H, s), 2.42 (2H, m),
2.15 (2H, m), 1.97
(2H, m), 1.76 (2H, m), 1.13 (3H, m).
Example 15
[0280] 6-{241-(5-Ethyl-pyrimidin-2-y1)-piperidin-4-y1]-thiazol-4-ylmethoxy}-
benzo[1,3]oxathio1-2-one
NJ N
N
'r 0 lei 0
[0281] 1HNMR (DMSO-d6): 6 8.23 (2H, s), 7.64 (1H, m), 7.62 (1H, s), 7.30 (1H,
m), 7.03
(1H, m), 5.14 (2H, s), 4.64 (2H, m), 3.31 (1H, m), 3.02 (2H, m), 2.40 (2H, q),
2.09 (2H, m), 1.58
(2H, m), 1.12 (3H, t).

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Example 16
[0282] 5-Ethy1-2-{444-(4-trifluoromethylsulfanyl-phenoxymethyl)-thiazol-2-y1]-
piperidin-1-
y1}-pyrimidine
F F
0 ipI
[0283] 1H NMR (DMSO-d6): 6 8.23 (2H, s), 7.63 (3H, m), 7.18 (2H, m), 5.17 (2H,
s), 4.67
(2H, m), 3.32 (1H, m), 3.01 (2H, m), 2.40 (2H, q), 2.08 (2H, m), 1.59 (2H, m),
1.13 (3H, t).
Example 17
[0284] 444-(3-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic
acid tert-butyl ester
=
ON-
/N
F
[0285] 1H NMR (CDC13): 6 9.04 (1H, s), 7.79 (1H, m), 7.29 (1H, s), 7.01 (2H,
m), 5.24 (2H, s),
4.22 (2H, m), 3.19 (1H, m), 2.89 (2H, m), 2.11 (2H, m), 1.74 (2H, m), 1.48
(9H, s).
Example 18
[0286] 444-(2-Fluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-
piperidine-1-
carboxylic acid tert-butyl ester
0
o¨ik/
µSr\o = i(i)
S-me
[0287] IIINMR (DMSO-d6): 6 7.79 (1H, m), 7.72 (1H, m), 7.70 (1H, s), 7.57 (1H,
m), 5.31
(2H, s), 3.99 (2H, m), 3.21 (3H, s), 3.20 (1H, m), 2.85 (2H, m), 2.02 (2H, m),
1.52 (2H, m), 1.39
(9H, s).
66

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Example 19
[0288] 444-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic
acid tert-butyl ester
F
ON1D0
N N
>ro
[0289] 1-14 NMR (CDC13): 6 8.98 (s, 1H), 7.53 (m, 1H), 7.44 (m, 1H), 7.31 (s,
1H), 7.27 (m,
1H), 5.31 (s, 2H), 4.21 (m, 2H), 3.16 (m, 1H), 2.89 (m, 2H), 2.11 (m, 2H),
1.74 (m, 2H), 1.47 (s,
9H) .
Example 20
[0290] 5-Ethy1-2-{444-(4-trifluoromethanesulfinyl-phenoxymethyl)-thiazol-2-y1]-
piperidin-1-
y1}-pyrimidine
N 0 lip FXF
S F
N
I
[0291] To a solution of 5-Ethy1-2-{4-[4-(4-trifluoromethylsulfanyl-
phenoxymethyl)-thiazol-2-
y1]-piperidin-1-y1}-pyrimidine (Example 16) in DCM at room temperature was
added 3-chloro-
benzenecarboperoxoic acid (2 eq.). The reaction was allowed to stir for 1.5
hours and an
additional portion of 3-chloro-benzenecarboperoxoic acid (1 eq.) was added to
the reaction
mixture. The reaction was stirred at room temperature for an additional 4
hours. The organic
solution was washed with sodium bicarbonate; the organic layer was isolated,
dried over sodium
sulfate and filtered. The filtrate was concentrated and the crude product was
purified by column
chromatography to afford the desired product. 1-H NMR (DMSO-d6): 6 8.40 (2H,
s), 7.58 (2H,
d), 7.22 (1H, s), 7.02 (2H, d,), 5.17 (2H, s), 3.74 (2H, m), 3.16 (1H, m),
2.96 (2H, m), 2.57 (2H,
m), 2.22 (4H, m), 1.24 (3H, m).
Example 21
67

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[0292] 444-(4-Methanesulfonyl-benzenesulfonylmethyl)-thiazol-2-y1]-piperidine-
1-carboxylic
acid tert-butyl ester
0
0)7,--N `611, s,o
[0293] To a solution of 444-(4-Methanesulfonyl-phenylsulfanylmethyl)-thiazol-2-
y1]-
piperidine-1-carboxylic acid tert-butyl ester (Example 8, 0.1 g, 0.21 mmol) in
CH2C12 (5 mL)
was added mCPBA (0.11 g, 0.42 mmol) at room temperature. The resulting mixture
was stirred
at room temperature for 2 hours and was washed with 5% NaHS03, saturated
NaHCO3 and
brine. The organic layer was dried with Na2SO4 and the solvent was removed in
vacuo. The
residue was purified by flash chromatography on silica gel to afford the
desired product. 11-1
NMR (CDC13): 6 8.03 (2H, d, J = 9.0 Hz), 7.88 (2H, d, J= 9.0 Hz), 7.29 (1H,
s), 4.57 (2H, s),
4.10 (2H, m), 3.07 (3H, s), 2.92 (1H, m), 2.75 (2H, m), 1.85 (2H, m), 1.46
(2H, m), 1.44 (9H, s).
Example 22
[0294] 444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid
isopropyl ester
0 0'41\7L '
[0295] To the HC1 salt (Intermediate 3, 43 mg, ¨0.12 mmol) of 444-(4-
Methanesulfonyl-
phenoxymethyl)-thiazol-2-y1]-piperidine was added 3 mL of THF, followed by
isopropyl
chloroformate (1.0 M solution in toluene, 0.15 mL, 0.15 mmol) and Et3N (0.05
mL). The
resulting mixture was stirred at room temperature for 2 hours, and then
partitioned between
Et0Ac and H20. After concentration of the organic layer in vacuo, the residue
was purified by
silica gel column chromatography with Et0Ac/hexanes (40-70%) to give the
desired product.
1H NMR (CDC13): 6 7.86 (2H, d, J= 9.0 Hz), 7.23 (1H, s), 7.11 (2H, d, J= 9.0
Hz), 5.22 (2H,
s), 4.92 (1H, m), 4.24 (2H, m), 3.17 (1H, m), 3.03 (3H, s), 2.90 (2H, m), 2.10
(2H, m), 1.72 (2H,
m), 1.23 (6H, d, J= 6.4 Hz).
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[0296] The compounds in Examples 23-46 were synthesized from one of
Intermediates 3-13
or Intermediates 15-25 with the corresponding sulfonyl chloride, alkyl
chloride, alkyl bromide,
chloroformate, acid chloride, carbamyl chloride or isocyanate in a manner
similar to that
described in Example 22. One skilled in the art of organic synthesis will
appreciate that
conditions such as solvent (e.g., DMF, CH3CN); temperature, base (e.g., NEt3,
K2CO3, NaHCO3,
Na2CO3, Cs2CO3) and concentration can be selected through routine
experimentation to
optimize yields. Additionally, alternative coupling methods can be used that
are well known in
the art of organic synthesis.
Example 23
[0297] 444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid
benzyl ester
N¨LO
0 N =
0
[0298] 1H NMR (CDC13): 6 7.87 (2H, d, J= 9.2 Hz), 7.31-7.37 (5H, m), 7.23 (1H,
s), 7.11
(2H, d, J= 9.2 Hz), 5.22 (2H, s), 5.14 (2H, s), 4.29 (2H, m), 3.16-3.22 (1H,
m), 3.03 (3H, s),
2.96 (2H, m), 2.12 (2H, m), 1.70-1.80 (2H, m).
Example 24
[0299] 444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid
isobutyl ester
0...--NO--k/(3
di
[0300] 1H NMR (CDC13): 6 7.87 (2H, d, J= 9.0 Hz), 7.23 (1H, s), 7.11 (2H, d, J
= 9.0 Hz),
5.22 (2H, s), 4.25 (2H, m), 3.87 (2H, d, J = 6.6 Hz), 3.17 (1H, m), 3.03 (3H,
s), 2.94 (2H, m),
2.12 (2H, m), 1.94 (1H, m), 1.75 (2H, m), 0.93 (6H, d, J= 6.6 Hz).
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Example 25
[0301] 444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid
adamantan-l-yl ester
S
0 0"---µ1\--
[0302] 1H Wit (CDC13): 6 7.89 (2H, d, J= 8.8 Hz), 7.24 (1H, s), 7.12 (2H, d, J
= 8.8 Hz),
5.23 (2H, s), 4.21 (2H, m), 3.12-3.20 (1H, m), 3.03 (3H, s), 2.87 (2H, m),
2.05-2.17 (11H, m),
1.62-1.79 (8H, m).
Example 26
[0303] 444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid
methyl ester
0...-N1D¨Z¨L
N 1110 s,
si
0
Me0
[0304] 1H Wit (CDC13): 6 7.87 (2H, d, J= 9.0 Hz), 7.23 (1H, s), 7.11 (2H, d, J
= 9.0 Hz),
5.22 (2H, s), 4.24 (2H, m), 3.71 (3H, s), 3.14-3.17 (1H, m), 3.03 (3H, s),
2.94 (2H, m), 2.12
(2H, m), 1.70-1.80 (2H, m).
Example 27
[0305] 444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid 4-
fluoro-phenyl ester
FO
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[0306] 111 NMR (CDC13): 6 7.88 (2H, d, J= 8.8 Hz), 7.12 (2H, d, J = 8.8 Hz),
7.01-7.09 (5H,
m), 5.24 (2H, s), 4.37 (2H, m), 3.23-3.27 (1H, m), 3.19 (2H, m), 3.04 (3H, s),
2.20 (2H, m),
1.88 (2H, m).
Example 28
[0307] 444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid 4-
methoxy-phenyl ester
0--Nia--4N =
S,
Me0 4Ik 0
[0308] 1H NMR (CDC13): 6 7.88 (2H, d, J= 8.2 Hz), 7.26 (1H, s), 7.12 (2H, d, J
= 8.6 Hz),
7.02 (2H, d, J = 8.6 Hz), 6.87 (2H, d, J = 8.2 Hz), 5.24 (2H, s), 4.38 (2H,
m), 3.79 (3H, s),
3.15-3.28 (3H, m), 3.03 (3H, s). 2.19 (2H, m), 1.87 (2H, m).
Example 29
[0309] 444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid
naphthalen-l-yl ester
0
01\-IL
s
0
[0310] IIINMR (CDC13): 6 7.88 (4H, m), 7.72 (1H, m), 7.49 (3H, m), 7.29 (2H,
m), 7.14 (2H,
m), 5.26 (2H, s), 4.64 (1H, m), 4.41 (1H, m), 3.34 (2H, m), 3.12 (1H, m), 3.04
(3H, s), 2.27 (2H,
m), 2.00 (2H, m).
Example 30
[0311] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid
isobutyl ester
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S
N 0 110
OyN N
NN
[0312] 1EINMR (CDC13): 6 8.94 (1H, s), 7.60 (2H, d), 7.24 (1H, s), 7.14 (2H,
d,), 5.20 (2H, s),
4.24 (2H, br), 3.85 (2H, d,), 3.18 (1H, m), 2.92 (2H, m), 2.11 (2H, m), 1.91
(1H, m), 1.75 (2H,
m), 0.91 (6H, d,).
Example 31
[0313] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid pentyl
ester
S
/N
Oy N N
0
[0314] 1H NMR (CDC13): 6 8.94 (1H, s), 7.62 (2H, d, J= 9.2 Hz), 7.28 (1H, s),
7.18 (2H, d, J
= 9.2 Hz), 5.24 (2H, s), 4.27 (2H, br), 4.09 (2H, m), 3.21 (1H, m), 2.94 (2H,
m), 2.14 (2H, m),
1.78 (2H, m), 1.65 (2H, m), 1.35 (4H, m), 0.91 (3H, m).
Example 32
[0315] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid 2-
fluoro-ethyl ester
S
7N
ON- N,
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[0316] 1H NMR (CDC13): 6 8.97 (1H, s), 7.62 (2H, d, J= 9.0 Hz), 7.28 (1H, s),
7.17 (2H, d, J
= 9.0 Hz), 5.24 (2H, s), 4.70-4.30 (6H, m), 3.22 (1H, m), 2.99 (2H, m), 2.15
(2H, m), 1.78 (2H,
m).
Example 33
[0317] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid butyl
ester
0 404 /N
IV,
NN
[0318] 1H NMR (CDC13): 6 9.01 (1H, s), 7.64 (2H, d, J= 8.8 Hz), 7.29 (1H, s),
7.17 (2H, d, J
= 8.8 Hz), 5.24 (2H, s), 4.26 (2H, m), 4.10 (2H, t), 3.21 (1H, m), 2.95 (2H,
m), 2.14 (2H, m),
1.78 (2H, m), 1.63 (2H, m), 1.40 (2H, m), 0.95 (3H, t, J= 7.4 Hz).
Example 34
[0319] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid 2,2-
dimethyl-propyl ester
0 410 /N
OyN N,
=NN
[0320] IIINMR (CDC13): 6 9.00 (1H, s), 7.56 (2H, d, J= 8.8 Hz), 7.21 (1H, s),
7.08 (2H, d, J
= 8.8 Hz), 5.14 (2H, s), 4.17 (2H, br), 3.69 (2H, s), 3.13 (1H, m), 2.88 (2H,
m), 2.06 (2H, m),
1.73 (2H, m), 0.86 (9H, s).
Example 35
[0321] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid hexyl
ester
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J-0 0 40
N 4N
[0322] 1H Wit (CDC13): 6 9.06 (1H, s), 7.65 (2H, d, J= 8.8 Hz), 7.29 (1H, s),
7.18 (2H, d, J
= 8.8 Hz), 5.24 (2H, s), 4.27 (2H, br), 4.09 (2H, t), 3.21 (1H, m), 2.95 (2H,
m), 2.14 (2H, m),
1.78 (2H, m), 1.64 (2H, m), 1.33 (6H, m), 0.89 (3H, m).
Example 36
[0323] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid 2-
ethyl-hexyl ester
S
N 0
N
OyN NN
0
[0324] 1H Wit (CDC13): 6 8.98 (1H, s), 7.58 (2H, d, J= 8.8 Hz), 7.23 (1H, s),
7.10 (2H, d, J
= 8.8 Hz), 5.17 (2H, s), 4.19 (2H, br), 3.95 (2H, m), 3.15 (1H, m), 2.89 (2H,
m), 2.07 (2H, m),
1.69 (2H, m), 1.52 (1H, m), 1.35-1.20 (8H, m), 0.90-0.80 (6H, m).
Example 37
[0325] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid 2-
benzyloxy-ethyl ester
0 40 0
N
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[0326] 1-14 NMIt (CDC13): 6 8.98 (1H, s), 7.57 (2H, d, J= 8.0 Hz), 7.30-
7.20(6H, m), 7.11
(2H, d, J= 8.0 Hz), 5.17 (2H, s), 4.52 (2H, s), 4.25-4.20 (4H, m), 3.65 (2H,
m), 3.15 (1H, m),
2.91 (2H, m), 2.08 (2H, m), 1.73 (2H, m).
Example 38
[0327] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid 2-
isopropy1-5-methyl-cyclohexyl ester
NN
/
Oy N NN
0
[0328] 1-14 NMIt (CDC13): 6 8.97 (1H, s), 7.58 (2H, m), 7.23 (1H, s), 7.11
(2H, m), 5.18 (2H,
s), 4.21 (2H, br), 3.13 (1H, m), 2.88 (2H, m), 2.05-0.70 (23H, m).
Example 39
[0329] Adamantan-l-yl-{444-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-
piperidin-l-
y1}-methanone
0 OSI\--IL/ s j:6N
[0330] 1-14 NMIt (CDC13): 6 7.88 (2H, d, J= 8.8 Hz), 7.24 (1H, s), 7.12 (2H,
d, J= 8.8 Hz),
5.23 (2H, s), 4.61 (2H, m), 3.24-3.30 (1H, m), 3.03 (3H, s), 2.93-3.00 (2H,
m), 2.16 (2H, m),
2.02-2.04 (9H, m), 1.70-1.80 (8H, m).
Example 40
[0331] {444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-A-piperidin-l-y1}-
pyridin-3-y1-
methanone

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0
0
N
S,
[0332] IIINMR (CDC13): 6 8.69 (2H, m), 7.88 (2H, d, J= 8.4 Hz), 7.79 (1H, m),
7.38 (1H,
m), 7.27 (1H, s), 7.12 (2H, d, J= 8.4 Hz), 5.24 (2H, s), 4.79 (2H, br), 3.86
(2H, br), 3.31 (1H,
m), 3.04 (3H, s), 2.20 (2H, m), 1.84 (2H, m).
Example 41
[0333] 3,3-Dimethy1-1-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidin-l-y1}-
butan-1-one
0 N 0 = N,Nr\ii
[0334] IIINMR (DMSO-d6): 6 9.98 (1H, s), 7.81 (2H, d, J= 8.8 Hz), 7.66 (1H,
s), 7.29 (2H,
d, J= 8.8 Hz), 5.20 (2H, s), 4.52 (1H, m), 4.10 (1H, m), 3.26 (1H, m), 3.19
(1H, m), 2.70 (1H,
m), 2.25 (2H, m), 2.15 (2H, m), 1.50 (2H, m), 0.96 (9H, s).
Example 42
[0335] Oxo-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-l-y1}-
acetic acid
methyl ester
0 N 0 ap,
0
[0336] IIINMR (DMSO-d6): 6 9.98 (1H, s), 7.81 (2H, d, J= 8.8 Hz), 7.68 (1H,
s), 7.29 (2H,
d, J= 8.8 Hz), 5.21 (2H, s), 4.32 (1H, m), 3.80 (3H, s), 3.60 (1H, m), 3.32
(1H, m), 2.94 (2H,
m), 2.13 (2H, m), 1.57 (2H, m).
Example 43
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[0337] 3 -Oxo-3 - {444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl] -
piperidin-l-y1} -propionic
acid ethyl ester
S
0 11 /N
N,
ON
NN
oY-
[0338] 1-14 NMR (DMSO-d6): 6 8.94 (1H, s), 7.61 (2H, m), 7.26 (1H, s), 7.15
(2H, m), 5.20
(2H, s), 4.65 (1H, m), 4.17 (2H, q), 3.87 (1H, m), 3.48 (2H, s), 3.26 (2H, m),
2.81 (1H, m), 2.18
(2H, m), 1.78 (2H, m), 1.27 (3H, t).
Example 44
[0339] (4-Methyl-piperazin-1-y1)-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-
2-A-
piperidin-1-y1 -methanone
Oy N 0
[0340] 1-14 NMR (DMSO-d6): 6 9.98 (1H, s), 7.81 (2H, d, J= 8.9 Hz), 7.64 (1H,
s), 7.29 (2H,
d), 5.20 (2H, s), 3.29 (2H, m), 3.18 (5H, m), 2.95 (2H, d), 2.61 (3H, s), 2.38
(2H, m), 2.03 (4H,
m), 1.65 (2H, m).
Example 45
[0341] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid
diethylamide
Oy N o, N
,N._
N
r
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[0342] IIINMR (DMSO-d6): 6 9.98 (1H, s), 7.81 (2H, d, J= 8.9 Hz), 7.66 (1H,
s), 7.29 (2H,
d, J = 8.9 Hz), 5.20 (2H, s), 3.55 (2H, m), 3.20 (1H, m), 3.14 (4H, q), 2.81
(2H, m), 2.02 (2H,
m), 1.64 (2H, m), 1.02 (6H, t, J= 6.8 Hz).
Example 46
[0343] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid
ethylamide
Oy N 0
NH
[0344] IIINMR (DMSO-d6): 6 9.98 (1H, s), 7.81 (2H, d, J= 8.9 Hz), 7.65 (1H,
s), 7.29 (2H,
d, J = 8.9 Hz), 6.47 (1H, m), 5.20 (2H, s), 4.01 (2H, d), 3.17 (1H, m), 3.04
(2H, m), 2.78 (2H,
m), 1.97 (2H, m), 1.52 (2H, m), 0.99 (3H, t, J= 6.8 Hz).
Example 47
[0345] 2-{444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidin-l-y1 -
pyrimidine
S
cNNI\vN
0 11,
I-
103461 A mixture of 444-(4-methylsulfonyl-phenoxymethyl)-thiazole-2-y1]-
piperidine
hydrochloride (100 mg, 0.24 mmol), 2-chloropyrimidine (30 mg, 1.1 eq.) and
diisopropylethylamine (122 mg, 4 eq.) in i-PrOH (5 mL) was heated at 90 C for
1.5 hours. The
solvent was removed in vacuo . The residue was purified on silica gel (60%
Et0Ac in hexanes)
to afford the desired product. 1-14 NMR (CDC13): 6 8.32 (2H, d, J= 4.8 Hz),
7.88 (2H, d, J = 8.8
Hz), 7.23 (1H, s), 7.12 (2H, d, J= 8.8 Hz), 6.49 (1H, t, J= 4.8 Hz), 5.24 (2H,
s), 4.89 (2H, m),
3.32 (1H, m), 3.06 (2H, m), 3.04 (3H, s), 2.22 (2H, m), 1.81 (2H, m).
[0347] The compounds in Examples 48-77 were synthesized from one of
Intermediates 3-13
or Intermediates 15-25 with the corresponding substituted 2-chloropyrimidine,
2-
iodopyrimidine, 2-chloropyridine, 2-fluoropyridine, 2-methanesulfonyl-
pyrimidine, 2-
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chloropyrazine, 2-chloropyridazine or other suitable heterocycles in a manner
similar to that
described in Example 47. One skilled in the art of organic synthesis will
appreciate that
conditions such as solvent (such as DIVIF, CH3CN); temperature, base (such as
NEt3, K2CO3,
NaHCO3, Na2CO3, Cs2CO3) and concentration can be selected through routine
experimentation
to optimize yields. Additionally, alternative coupling methods can be used
that are well known
in the art of organic synthesis.
Example 48
[0348] 2-{444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidin-1-y1 -
4-methoxy-
pyrimidine
N
--N 0 NOQTh 110 0
0
0
[0349] 1-14 NMR (CDC13): 6 8.06 (1H, d, J= 6.0 Hz), 7.87 (2H, d, J = 8.8 Hz),
7.23 (1H, s),
7.12 (2H, d, J = 8.8 Hz), 5.98 (1H, d, J = 6.0 Hz), 5.24 (2H, s), 4.88 (2H,
m), 3.90 (3H, s), 3.31
(1H, m), 3.04 (5H, m), 2.20 (2H, m), 1.81 (2H, m).
Example 49
[0350] 2-{444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidin-1-y1 -
4-
trifluoromethyl-pyrimidine
N1Th
N
0
[0351] 1-14 NMR (CDC13): 6 8.50 (1H, d, J= 4.8 Hz), 7.88 (2H, d, J= 8.8 Hz),
7.24 (1H, s),
7.12 (2H, d, J = 8.8 Hz), 6.76 (1H, d, J = 4.8 Hz), 5.24 (2H, s), 4.92 (2H,
m), 3.34 (1H, m), 3.11
(2H, m), 3.04 (3H, s), 2.24 (2H, m), 1.84 (2H, m).
Example 50
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[0352] 2-{444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidin-l-y1}-
4,6-
dimethyl-pyrimidine
Nj
0 = p
S¨
O
[0353] 1-14 NMR (CDC13): 6 7.88 (2H, d, J= 8.4 Hz), 7.22 (1H, s), 7.12 (2H, d,
J= 8.4 Hz),
6.27 (1H, s), 5.24 (2H, s), 4.96 (2H, m), 3.28 (1H, m), 3.04 (3H, s), 2.99
(2H, m), 2.29 (6H, s),
2.19 (2H, m), 1.80 (2H, m).
Example 51
[0354] 5-Ethy1-2-{444-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-A-piperidin-
l-y1}-
pyrimidine
0 104 0
--N
it
0
[0355] 1-14 NMR (CDC13): 6 8.19 (2H, s), 7.87 (2H, d, J= 8.8 Hz), 7.22 (1H,
s), 7.12 (2H, d, J
= 8.8 Hz), 5.24 (2H, s), 4.84 (2H, m), 3.30 (1H, m), 3.04 (2H, m), 3.03 (3H,
s), 2.47 (2H, q, J=
7.2 Hz), 2.22 (2H, m), 1.81 (2H, m), 1.20 (3H, t, J= 7.2 Hz).
Example 52
[0356] 5-Ethy1-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-A-piperidin-l-
y1}-
pyrimidine
S¨\_\
1\1/
N N
r 0 *
NN
[0357] 1-14 NMR (DMSO-d6): 6 9.98 (1H, s), 8.24 (2H, s), 7.80 (2H, d, J= 8.8
Hz), 7.66 (1H,
s), 7.28 (2H, d, J= 8.8 Hz), 5.20 (2H, s), 4.67 (2H, m), 3.32 (1H, m), 3.01
(2H, m), 2.43 (2H, q,
J= 7.2 Hz), 2.07 (2H, m), 1.59 (2H, m), 1.11 (3H, t, J= 7.2 Hz).

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Example 53
[0358] 5-Fluoro-2-{444-(6-tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-A-
piperidin-l-y1}-
pyrimidine
S
F
N
1\1
N \=N
[0359] IIINMR (DMSO-d6): 6 10.07 (1H, s), 8.43 (2H, s), 8.41 (1H, d, J= 3.2
Hz), 7.98 (1H,
d, J= 9.2 Hz), 7.86 (1H, dd, J= 9.2, 3.2 Hz), 7.71 (1H, s), 5.30 (2H, s), 4.58
(2H, m), 3.31 (1H,
m), 3.01 (2H, m), 2.10 (2H, m), 1.59 (2H, m).
Example 54
[0360] 5-Bromo-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
l-y1}-
pyrimidine
S¨\ 0
N
NN
1\1=-Ni
[0361] IIINMR (CDC13): 6 8.90 (1H, s), 8.29 (2H, s), 7.60 (2H, d, J= 9.0 Hz),
7.25 (1H, s),
7.16 (2H, d, J= 9.0 Hz), 5.23 (2H, s), 4.81 (2H, m), 3.31 (1H, m), 3.06 (2H,
m), 2.21 (2H, m),
1.79 (2H, m).
Example 55
[0362] 5-Fluoro-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
l-y1}-
pyrimidine
z\ 0
ND-N¨ 111110 ,N
N "N
F _.- 4
N
81

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[0363] 1-14 NMR (CDC13): 6 8.91 (1H, s), 8.20 (2H, s), 7.60 (2H, d, J= 8.6
Hz), 7.25 (1H, s),
7.16 (2H, d, J= 8.6 Hz), 5.23 (2H, s), 4.78 (2H, m), 3.31 (1H, m), 3.06 (2H,
m), 2.21 (2H, m),
1.83 (2H, m).
Example 56
[0364] 4,5-Dichloro-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidin-1-y1}-
pyrimidine
çNN911110 ,N
N
N "
CI S \
N
CI
[0365] 1-14 NMR (CDC13): 6 8.91 (1H, s), 8.10 (1H, s), 7.61 (2H, d, J= 8.8
Hz), 7.27 (1H, s),
7.16 (2H, d, J= 8.8 Hz), 5.23 (2H, s), 4.62 (2H, m), 3.34 (1H, m), 3.18 (2H,
m), 2.25 (2H, m),
1.98 (2H, m).
Example 57
[0366] 4-Chloro-5-methy1-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-A-
piperidin-1-
y1 -pyrimidine
,N
N "/
Me N --N
CI
[0367] 1-14 NMR (CDC13): 6 8.90 (1H, s), 8.08 (1H, s), 7.60 (2H, d, J= 8.8
Hz), 7.24 (1H, s),
7.17 (2H, d, J= 8.8 Hz), 5.23 (2H, s), 4.80 (2H, m), 3.30 (1H, m), 3.04 (2H,
m), 2.19 (2H, m),
2.16 (3H, s), 1.81 (2H, m).
Example 58
[0368] 2-Chloro-5-methy1-4-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-A-
piperidin-1-
y1 -pyrimidine
82

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Me
111110 ,N
Nr N "N
CI N
[0369] IIINMR (CDC13): 6 8.92 (1H, s), 7.96 (1H, s), 7.60 (2H, d, J= 8.8 Hz),
7.27 (1H, s),
7.16 (2H, d, J= 8.8 Hz), 5.23 (2H, s), 4.17 (2H, m), 3.31 (1H, m), 3.10 (2H,
m), 2.26 (2H, m),
2.21 (3H, s), 1.95 (2H, m).
Example 59
[0370] 5-(4-Chloro-pheny1)-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-
y1]-piperidin-
l-y1 -pyrimidine
404
NrN
CI --N
[0371] IIINMR (DMSO-d6): 6 9.97 (1H, s), 8.71 (2H, s), 7.80 (2H, d, J= 8.8
Hz), 7.67 (2H,
d, J= 8.4 Hz), 7.66 (1H, s), 7.48 (2H, d, J= 8.4 Hz), 7.28 (2H, d, J= 8.8 Hz),
5.21 (2H, s), 4.76
(2H, m), 3.37 (1H, m), 3.13 (2H, m), 2.12 (2H, m), 1.66 (2H, m).
Example 60
[0372] 5-Chloro-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
l-y1 -
pyrimidine
rN/Tho
N N
NN
µ1\1=-1\j
[0373] IIINMR (CDC13): 6 8.91 (1H, s), 8.23 (2H, s), 7.61 (2H, d, J= 8.8 Hz),
7.26 (1H, s),
7.17 (2H, d, J= 8.8 Hz), 5.24 (2H, s), 4.82 (2H, m), 3.32 (1H, m), 3.07 (2H,
m), 2.22 (2H, m),
1.81 (2H, m).
Example 61
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[0374] 5-Hepty1-2-{444-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-
piperidin-l-y1}-
pyrimidine
faN_4--L CH
0
---N
[0375] 1H Wit (CDC13): 6 8.16 (2H, s), 7.87 (2H, d, J= 9.0 Hz), 7.22 (1H,
s),7.12 (2H, d, J=
9.0 Hz), 5.24 (2H, s), 4.83 (2H, m), 3.29 (1H, m), 3.04 (2H, m), 3.03 (3H, s),
2.42 (2H, t, J= 7.4
Hz), 2.21 (2H, m), 1.80 (2H, m), 1.52 (2H, m), 1.28 (8H, m), 0.89 (3H, t).
Example 62
[0376] 2-{444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidin-l-y1}-
5-pentyl-
pyrimidine
fiNJ 'NS-rjA
-3
0
[0377] 1H Wit (CDC13): 6 8.16 (2H, s), 7.87 (2H, d, J= 8.8 Hz), 7.22 (1H,
s),7.12 (2H, d, J=
8.8 Hz), 5.23 (2H, s), 4.83 (2H, m), 3.29 (1H, m), 3.04 (2H, m), 3.03 (3H, s),
2.42 (2H, t, J= 7.6
Hz), 2.21 (2H, m), 1.81 (2H, m), 1.56 (2H, m), 1.32 (4H, m), 0.90 (3H, t).
Example 63
[0378] 5-Hepty1-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
l-y1}-
pyrimidine
04¨NL0
NyN
1\1=K1
--N
[0379] 1H Wit (CDC13): 6 8.90 (1H, s), 8.16 (2H, s), 7.60 (2H, d, J= 8.8 Hz),
7.24 (1H, s),
7.17 (2H, d, J= 8.8 Hz), 5.23 (2H, s), 4.82 (2H, m), 3.29 (1H, m), 3.04 (2H,
m), 2.42 (2H, t),
2.20 (2H, m), 1.80 (2H, m), 1.53 (2H, m), 1.28 (8H, m), 0.87 (3H, t).
Example 64
84

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[0380] 5-Penty1-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
l-y1}-
pyrimidine
Na4N-L 1110 N N
1\1=KI
[0381] 1H Wit (CDC13): 6 8.90 (1H, s), 8.16 (2H, s), 7.60 (2H, d, J= 8.8 Hz),
7.24 (1H, s),
7.17 (2H, d, J= 8.8 Hz), 5.23 (2H, s), 4.83 (2H, m), 3.30 (1H, m), 3.04 (2H,
m), 2.42 (2H, t),
2.20 (2H, m), 1.80 (2H, m), 1.54 (2H, m), 1.30 (4H, m), 0.89 (3H, t).
Example 65
[0382] 5-Methy1-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidin-l-y1}-
pyrimidine
1\)Th
0 =N N
[0383] 1H Wit (CDC13): 6 8.94 (1H, s), 8.17 (2H, s), 7.62 (2H, d, J= 8.8 Hz),
7.25 (1H, s),
7.17 (2H, d, J= 8.8 Hz), 5.24 (2H, s), 4.82 (2H, d), 3.30 (1H, m), 3.04 (2H,
m), 2.22 (2H, m),
2.13 (3H, s), 1.81 (2H, m).
Example 66
[0384] 5-(4-Methoxy-pheny1)-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-
y1]-
piperidin-l-y1}-pyrimidine
N 40,
/
h1=K1
N
Me

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[0385] IIINMR (CDC13): 6 8.90 (1H, s), 8.52 (s, 2H), 7.61 (2H, d, J= 9.0 Hz),
7.41 (2H, d, J
= 8.6 Hz), 7.25 (1H, s), 7.17 (2H, d, J= 9.0 Hz), 6.99 (2H, d, J= 8.6 Hz),
5.24 (2H, s), 4.92 (2H,
m), 3.85 (3H, s), 3.34 (1H, m), 3.12 (2H, m), 2.25 (2H, m), 1.85 (2H, m) .
Example 67
[0386] 5-Propy1-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-A-piperidin-l-
y1}-
pyrimidine
SITh
N N
0
N
[0387] 1H NMR (CDC13): 6 8.9 (1H, s), 8.17 (2H, s), 7.61 (2H, d, J= 8.8 Hz),
7.24 (1H, s),
7.17 (2H, d, J= 8.8 Hz), 5.24 (2H, s), 4.83 (2H, m), 3.31 (1H, m), 3.04 (2H,
m), 2.4 (2H, t, J=
7.6 Hz), 2.22 (2H, m), 1.81 (2H, m), 1.58 (2H, m), 0.94 (3H, t, J= 7.6 Hz).
Example 68
[0388] 5-Methoxy-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidin-l-y1}-
pyrimidine
SITh
o, N N
[0389] 1H NMR (CDC13): 6 8.93 (1H, s), 8.11 (2H, s), 7.61 (2H, d, J= 8.8 Hz),
7.25 (1H, s),
7.17 (2H, d, J= 8.8 Hz), 5.24 (2H, s), 4.74 (2H, m), 3.81 (3H, s), 3.31 (1H,
m), 3.03 (2H, m),
2.22 (2H, m), 1.82 (2H, m).
Example 69
[0390] 5'-Methy1-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-3,4,5,6-
tetrahydro-2H-
[1,2']bipyridinyl
86

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0 410
N N
Nz--N1
[0391] IIINMR (CDC13): 6 8.91 (1H, s), 8.03 (1H, m), 7.61 (2H, m), 7.33 (1H,
m), 7.26 (1H,
s), 7.18 (2H, m), 6.65 (1H, d, J= 8.8 Hz), 5.24 (2H, s), 4.33 (2H, m), 3.25
(1H, m), 2.97 (2H,
m), 2.22 (2H, m), 2.21 (3H, s), 1.89 (2H, m).
Example 70
[0392] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-5',6"-bis-
trifluoromethy1-3,4,5,6-
tetrahydro-2H-[1,2';6',2"]terpyridine
N NON 0
m
F3C N N
F3C
[0393] 1H NMR (DMSO-d6): 6 8.81 (1H, m), 8.39 (1H, m), 8.13 (1H, dd, J= 8.8,
2.4 Hz),
7.76 (1H, dd, J = 8.8, 2.8 Hz), 7.66 (1H, s), 7.59 (2H, m), 7.25 (2H, m), 6.99
(1H, d, J= 9 Hz),
6.8 (1H, d, J= 9 Hz), 5.19 (2H, s), 4.48 (2H, d), 3.37 (1H, m), 3.10 (2H, m),
2.11(2H, m), 1.65
(2H, m).
Example 71
[0394] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-5'-trifluoromethy1-
3,4,5,6-
tetrahydro-2H-[1,2']bipyridinyl
S--\\
NJ
0
110 N
F3CN.NN
87

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[0395] IIINMR (DMSO-d6): 6 9.98 (1H, s), 8.40 (1H, m), 7.81-7.75 (3H, m), 7.66
(1H, s),
7.28 (2H, d), 6.99 (1H, d, J= 8.8 Hz), 5.21 (2H, s), 4.48 (2H, d), 3.37 (1H,
m), 3.1 (2H, m), 2.12
(2H, m), 1.65 (2H, m).
Example 72
[0396] 4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-3,4,5,6-tetrahydro-
2H-
[1,21bipyridiny1-5'-carbaldehyde
j1\-1-Th
N N
0 =
NN
N
oI
[0397] 1-1-1NMR (DMSO-d6): 6 9.98 (1H, s), 9.72 (1H, s), 8.58 (1H, d, J = 2.4
Hz), 7.86 (1H,
dd, J = 9.2, 2 Hz), 7.8 (2H, d, J = 8.4 Hz), 7.67 (1H, s), 7.28 (2H, d, J= 8.4
Hz), 6.99 (1H, d, J=
8.8 Hz), 5.2 (2H, s), 4.58 (2H, d), 3.41 (1H, m), 3.17 (2H, m), 2.13 (2H, m),
1.65 (2H, m).
Example 73
[0398] 1-(3-Isopropy141,2,4]oxadiazol-5-y1)-444-(4-methanesulfonyl-
phenoxymethyl)-
thiazol-2-y1]-piperidine
0
=
0 11
0
N-0
0
[0399] 1-1-1NMR (CDC13): 6 7.87 (2H, m), 7.26 (1H, s), 7.11 (2H, m), 5.23 (2H,
s), 4.76-4.68
(1H, m), 4.26-4.18 (1H, m), 3.4-3.3 (2H, m), 3.2-3.04 (2H, m), 3.03 (3H, s),
2.32-2.2 (2H, m),
2.00-1.86 (2H, m), 1.36 (6H, d, J= 7.2 Hz).
Example 74
[0400] 2-{444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidin-l-y1}-
benzooxazole
88

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S--\\ = 0
N P
= N
[0401] 111 NMR (CDC13): 6 7.87 (2H, d, J = 8.4 Hz), 7.36 (1H, d, J = 7.6 Hz),
7.01-7.19 (6H,
m), 5.24 (2H, s), 4.42 (2H, m), 3.30 (3H, m), 3.03 (3H, s), 2.27 (2H, m), 1.95
(2H, m).
Example 75
[0402] 444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-5'-trifluoromethy1-
3,4,5,6-
tetrahydro-2H-[1,21bipyridinyl
0
1\1 \O =
0
N
FF N
[0403] IIINMR (CDC13): 6 8.4 (1H, s), 7.87 (2H, d), 7.63 (1H, m), 7.26 (1H,
s), 7.12 (2H, d),
6.69 (1H, d), 5.23 (2H, s), 4.55-4.50 (2H, m), 3.38-3.28 (1H, m), 3.20-3.10
(2H, m), 3.04 (3H,
s), 2.30-2.20 (2H, m), 1.90-1.80 (2H, m).
Example 76
[0404] 5-Ethy1-2-{444-(2-fluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-
piperidin-
l-y1}-pyrimidine
S
N me 1110 /CP
N S-
Et ...--N
[0405] 1H NMR (CDC13): 6 8.18 (2H, s), 7.65-7.70 (2H, m), 7.21-7.26 (2H, m),
5.30 (2H, s),
4.81-4.84 (2H, m), 3.25-3.28 (1H, m), 3.03 (3H, s), 3.00-3.07 (2H, m), 2.44
(2H, q), 2.21 (2H,
m), 1.77-1.81 (2H, m), 1.19 (3H, t).
Example 77
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[0406] 5-Ethy1-2-{444-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidin-1-
y1 -pyrimidine
S--\\
N N
r-C-N 0
N
N=14
[0407] 1H NMIR (CDC13): 6 8.96 (1H, s), 8.19 (2H, s), 7.55-7.25 (4H, m), 5.31
(2H, s), 4.82
(2H, m), 3.30 (1H, m), 3.04 (2H, m), 2.47 (2H, q), 2.23 (2H, m), 1.81 (2H, m),
1.20 (3H, t).
Example 78
[0408] 444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-4-methyl-piperidine-
1-
carboxylic acid tert-butyl ester
3__/0 =
0),N sO
0
[0409] Step 1: 4-Cyano-4-methyl-piperidine-1-carboxylic acid tert-butyl ester
0 \
N
y o __ CN
[0410] To a solution of 4-cyano-piperidine-1-carboxylic acid tert-butyl ester
(4.52 g, 20
mmol) in THF (50 mL) was added LHMDS in THF (24 mL, 24 mmol) at 0 C. After
stirring at
0 C for 1 hour, Mel (5.7 g) was added. The reaction mixture was kept at 0 C
for 2 hours, then
partitioned between Et0Ac and H20. After concentration in vacuo, the residue
was purified by
silica column chromatography with Et0Ac/hexanes to give the desired product.
[0411] Step 2: 4-Carbamoy1-4-methyl-piperidine-1-carboxylic acid tert-butyl
ester
N )cNH
\ 2
0
[0412] To a solution of 4-cyano-4-methyl-piperidine-1-carboxylic acid tert-
butyl ester (2.24 g,
mmol) in methanol (25 mL) was added DMSO (1 mL), aqueous 1 N NaOH (12 mL, 12

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mmol) and H202 (4 mL) at room temperature. The mixture was heated at 50 C for
3 hours.
After cooling to room temperature, the mixture was partitioned between Et0Ac
and H20. The
organic layer was washed successively with H20 and brine. After drying
(Na2SO4), the solvent
was removed to afford the desired product.
[0413] Step 3: 4-Methy1-4-thiocarbamoyl-piperidine-1-carboxylic acid tert-
butyl ester
0 /
N\
NH2
[0414] To a solution of 4-carbamoy1-4-methyl-piperidine-1-carboxylic acid tert-
butyl ester
(2.1 g, 8.7 mmol) in THF (30 mL) was added Lawesson's reagent (3.5 g, 8.7
mmol) at room
temperature. The mixture was heated at 50 C for 3 hours. After cooling to room
temperature,
the solvent was removed in vacuo and the residue was partitioned between Et0Ac
and H20.
The organic layer was washed with saturated NaHCO3, and brine. After drying
(Na2SO4), the
solvent was removed in vacuo, and the residue was purified by silica column
chromatography
with Et0Ac/hexanes to afford the desired product.
[0415] Step 4: 4-(4-Ethoxycarbonyl-thiazol-2-y1)-4-methyl-piperidine-1-
carboxylic acid tert-
butyl ester
0
/
7 _____________________________ N 0
X0 \
[0416] To a solution of 4-methy1-4-thiocarbamoyl-piperidine-1-carboxylic acid
tert-butyl ester
(1 g, 4 mmol) in Et0H (10 mL) was added ethyl bromopyruvate (0.78 g, 4 mmol)
at room
temperature. The mixture was heated to refluxing for 3 hours. After cooling to
room
temperature, the solvent was removed in vacuo. The residue was dissolved in
methylene
chloride (15 mL), Et3N (1 mL) and di-tert-butyl dicarbonate (1.3 g) were added
to the solution.
The mixture was stirred at room temperature overnight. The mixture was washed
with H20 and
brine. After drying (Na2SO4), the solvent was removed in vacuo, and the
residue was purified
by silica column chromatography with Et0Ac/hexanes to afford the desired
product.
[0417] Step 5: 4-(4-Hydroxymethyl-thiazol-2-y1)-4-methyl-piperidine-1-
carboxylic acid tert-
butyl ester
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0
X0' N/--)c---N ______________________________
S---1 OH
[0418] To a solution of 4-(4-ethoxycarbonyl-thiazol-2-y1)-4-methyl-piperidine-
1-carboxylic
acid tert-butyl ester (0.6 g, 1.7 mmol) in anhydrous THF (10 mL) was added
LiA1H4 (0.1 g, 2.6
mmol) at 0 C. The mixture was kept at 0 C for 2 hours and the reaction was
quenched with
Et0H. The solvent was evaporated and the residue was diluted with Et0Ac,
washed with 1 N
NaOH, brine. After drying (Na2SO4), the solvent was removed in vacuo, and the
residue was
purified by silica column chromatography with Et0Ac/hexanes to afford the
desired product.
[0419] Step 6: 4-(4-Methanesulfonyloxymethyl-thiazol-2-y1)-4-methyl-piperidine-
1-
carboxylic acid tert-butyl ester
0
0\ /
0¨s
X ___________________________ N
0> _______________________________
S = 0
[0420] To a solution of 4-(4-hydroxymethyl-thiazol-2-y1)-4-methyl-piperidine-1-
carboxylic
acid tert-butyl ester (0.42 g, 1.3 mmol) in methylene chloride (10 mL) was
added
methanesulfonyl chloride (0.19 g, 1.7 mmol) and triethylamine (0.2 g, 2 mmol)
at 0 C. After
stirring at 0 C for 1 hour, the mixture was diluted with Et0Ac and washed with
H20 and brine.
After drying (Na2SO4), the solvent was removed in vacuo, and the residue was
purified by silica
column chromatography with Et0Ac/hexanes to afford the desired product.
[0421] Step 7: 444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-4-methyl-
piperidine-1-
carboxylic acid tert-butyl ester
LO
0)r-N
0
0
[0422] A mixture of 4-(4-methanesulfonyloxymethyl-thiazol-2-y1)-4-methyl-
piperidine-1-
carboxylic acid tert-butyl ester (0.2 g, 0.5 mmol), 4-methanesulfonyl-phenol
(86 mg, 0.5 mmol)
and Cs2CO3 (170 mg, 0.52 mmol) in acetonitrile (4 mL) was heated at 40 C
overnight. After
cooling, the solid was filtered through a pad of celite. The filtrate was
concentrated in vacuo.
The residue was purified on silica gel (Et0Ac-hexanes, 1:1) to afford the
desired product. 11-1
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NMR (CDC13): 6 7.83 (2H, m), 7.23 (1H, s), 7.09 (2H, m), 5.2 (2H, s), 3.64-
3.54 (2H, m),
3.3-3.24 (2H, m), 2.99 (3H, s), 2.2-2.1 (2H, m), 1.72-1.64(2H, m), 1.41 (9H,
s), 1.36 (3H, s).
Example 79
[0423] 444-(4-Methanesulfonyl-phenoxymethyl)-5-methyl-thiazol-2-y1]-piperidine-
1-
carboxylic acid tert-butyl ester
0
\O
OiN
[0424] To a solution of 4-(4-hydroxymethy1-5-methyl-thiazol-2-y1)-piperidine-1-
carboxylic
acid tert-butyl ester (0.18 g, 0.6 mmol), 4-methanesulfonyl-phenol (0.1 g, 0.6
mmol) and PPh3
(0.19 g, 0.72 mmol) in THF (5 mL) was added diethylazodicarboxylate (DEAD)
(0.22 g, 0.72
mmol) at room temperature. The resulting mixture was stirred at room
temperature for 30
minutes. The solvent was removed and the residue was purified by flash
chromatography on
silica gel to afford the desired product. IIINMR (CDC13): 6 7.9 (2H, d, J= 9
Hz), 7.09 (2H, d, J
= 9 Hz), 5.2 (2H, s), 4.28-4.10 (2H, m), 3.14-3.04 (1H, m), 3.04 (3H, s), 2.9-
2.8 (2H, m), 2.44
(3H, s), 2.1-2 (2H, m), 1.76-1.64 (2H, m), 1.47 (9H, s).
Example 80
[0425] 4-{441-(4-Methanesulfonyl-phenoxy)-ethy1]-5-methyl-thiazol-2-y1} -
piperidine-1-
carboxylic acid tert-butyl ester
0
\O 411
oyN
v
[0426] Step 1: 444-(1-Hydroxy-ethyl)-5-methyl-thiazol-2-y1]-piperidine-1-
carboxylic acid
tert-butyl ester
93

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HO N
0
[0427] To a solution of 4-(4-formy1-5-methyl-thiazol-2-y1)-piperidine-1-
carboxylic acid tert-
butyl ester (0.31 g, 1 mmol) in THF (10 mL) was added MeMgI (1 mL, 3 mmol) in
Et20 at
room temperature. The resulting mixture was stirred at room temperature for 1
hour. The
reaction was quenched with saturated aqueous NH4C1 and extracted with Et0Ac.
The organic
layer was washed with H20 and brine. After drying over Na2SO4, the solvent was
removed.
The residue was purified by flash chromatography on silica gel to afford the
desired product.
[0428] Step 2: 4-{441-(4-Methanesulfonyl-phenoxy)-ethy1]-5-methyl-thiazol-2-
y1} -
piperidine-1-carboxylic acid tert-butyl ester
N 41 S-
i
0
N
0
[0429] To a solution of 444-(1-Hydroxy-ethyl)-5-methyl-thiazol-2-y1]-
piperidine-1-carboxylic
acid tert-butyl ester (0.15 g, 0.46 mmol), 4-methanesulfonyl-phenol (0.08 g,
0.46 mmol) and
PPh3(0.14 g, 0.55 mmol) in THF (5 mL) was added DEAD (0.1 g, 0.55 mmol) at
room
temperature. The resulting mixture was stirred at room temperature for 30
minutes. The solvent
was removed. The residue was purified by flash chromatography on silica gel to
afford the
desired product. 11-1NMR (CDC13): 6 7.79 (2H, m), 6.94 (2H, m), 5.59 (1H, q,
J= 6 Hz), ), 4.2-
4.04 (2H, m), 3.04-2.94 (1H, m), 2.98 (3H, s), 2.86-2.72 (2H, m), 2.39 (3H,
s), 2.04-1.96 (2H,
m), 1.67 (3H, d, J= 6 Hz), 1.66-1.58 (2H, m), 1.42 (9H, s).
Example 81
[0430] 443-(4-Methanesulfonyl-phenoxymethy1)41,2,4]oxadiazol-5-y1]-piperidine-
1-
carboxylic acid tert-butyl ester
94

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O-N
\ 0
N 0 11
>10
Oy N
[0431] Step 1: N-Hydroxy-2-(4-methanesulfonyl-phenoxy)-acetamidine
HO\
NH
0
/
¨S ''O NH
1 I.
0
[0432] To a mixture of (4-methanesulfonyl-phenoxy)-acetonitrile (2 g, 9.5
mmol), K2CO3 (1.3
g, 9.5 mmol) in H20 (30 mL) and Et0H (15 mL) was added hydroxylamine
hydrogenchloride
(1.32 g, 19 mmol). The mixture was heated under reflux overnight, cooled and
ethanol was
removed in vacuo and the residue was extracted with Et0Ac (150 mL). The
organic layer was
washed successively with H20 and brine. After drying (Na2SO4), the solvent was
removed to
afford the desired product.
[0433] Step 2: 443-(4-Methanesulfonyl-phenoxymethy1)41,2,4]oxadiazol-5-y1]-
piperidine-1-
carboxylic acid tert-butyl ester
O'N
0
N 0=

s ¨
oy N
[0434] To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester
(2.06 g, 9
mmol), NEt3 ( 1.2 g, 12 mmol) in toluene (150 mL) was added
isobutylchloroformate (1.23 g, 9
mmol) at 0 C. The mixture was stirred at room temperature for 1.5 hours. N-
hydroxy-2-(4-
methanesulfonyl-phenoxy)-acetamidine (1.5 g, 6 mmol) was added to the mixture.
The mixture
was heated under reflux overnight, cooled and the mixture was washed
successively with H20
and brine. After drying (Na2SO4), the solvent was removed. The residue was
purified by flash
chromatography on silica gel to afford the desired product. 1-14 NMR (CDC13):
6 7.98 (2H, m),

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7.14 (2H, m), 5.24 (2H, s), 4.2-4.05 (2H, m), 3.14 (1H, m), 3.03 (3H, s), 2.95
(2H, m),
2.12-2.04 (2H, m), 1.80 (2H, m), 1.46 (9H, s).
Example 82
[0435] 445-(4-Methanesulfonyl-phenoxymethy1)41,2,4]oxadiazol-3-y1]-piperidine-
1-
carboxylic acid tert-butyl ester
N-0
N
0
0 N
0
>0
[0436] Step 1: 4-(N-Hydroxycarbamimidoy1)-piperidine-1-carboxylic acid tert-
butyl ester
N-OH
NH2
0 N
y
>c)
[0437] To a mixture of 4-cyano-piperidine-1-carboxylic acid tert-butyl ester
(6.3 g, 30 mmol),
K2CO3 (4.2 g, 30 mmol) in H20 (50 mL) and Et0H (30 mL) was added hydroxylamine

hydrogenchloride (4.17 g, 60 mmol). The mixture was heated under reflux
overnight, cooled to
room temperature and ethanol was removed in vacuo. The residue was extracted
with Et0Ac
(300 mL). The organic layer was washed successively with H20 and brine. After
drying
(Na2SO4), the solvent was removed to afford the desired product.
[0438] Step 2: 4-(5-Hydroxymethy141,2,4]oxadiazol-3-y1)-piperidine-1-
carboxylic acid tert-
butyl ester
N-0
OH
0 NI_
>C1
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[0439] To a solution of hydroxy-acetic acid (1.67 g, 22 mmol), NEt3 (4.4 g, 44
mmol) in
toluene (150 mL) was added isobutylchloroformate (6 g, 44 mmol) at 0 C. The
mixture was
stirred at room temperature for 1.5 hours. 4-(N-Hydroxycarbamimidoy1)-
piperidine-1-
carboxylic acid tert-butyl ester (5.35 g, 22 mmol) was added to the mixture.
The mixture was
heated under reflux overnight, and then cooled to room temperature; the
mixture was washed
successively with H20 and brine. After drying (Na2SO4), the solvent was
removed. The residue
was dissolved in THF (20 mL), and aqueous NaOH (10 mL, 10 mmol) was added. The
mixture
was stirred at room temperature for 2 hours and diluted with Et0Ac (50 mL).
The organic layer
was washed with brine, after drying (Na2SO4), the solvent was removed in
vacuo, and the
residue was purified by silica column chromatography with Et0Ac/hexanes to
afford the desired
product.
[0440] Step 3: 4-(5-Methanesulfonyloxymethy141,2,4]oxadiazol-3-y1)-piperidine-
1-
carboxylic acid tert-butyl ester
N-0
0-S-
Oy N 8
[0441] To a solution of 4-(5-hydroxymethy141,2,4]oxadiazol-3-y1)-piperidine-1-
carboxylic
acid tert-butyl ester (0.2 g, 0.7 mmol) in methylene chloride (5 mL) was added
methanesulfonyl
chloride (0.1 g, 0.9 mmol) and triethyl amine (0.14 g, 1.4 mmol) at 0 C. After
stirred at 0 C for
1 hour, the mixture was diluted with Et0Ac and washed with H20, brine. After
drying
(Na2SO4), the solvent was removed in vacuo, and the residue was purified by
silica column
chromatography with Et0Ac/hexanes to afford the desired product
[0442] Step 4: 445-(4-Methanesulfonyl-phenoxymethy1)41,2,4]oxadiazol-3-y1]-
piperidine-1-
carboxylic acid tert-butyl ester
N-0
0 IF 9,
0-
Oy N
8
>101
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[0443] A mixture of 4-(5-methanesulfonyloxymethy141,2,4]oxadiazol-3-y1)-
piperidine-1-
carboxylic acid tert-butyl ester (0.12 g, 0.33 mmol), 4-methanesulfonyl-phenol
(86 mg, 0.5
mmol) and Cs2CO3 (0.33 g, 1 mmol) in acetonitrile (5 mL) was heated at 50 C
for 2 hours.
After cooling, the solid was filtered through a pad of celite. The filtrate
was concentrated in
vacuo. The residue was purified on silica gel (Et0Ac-hexanes, 1:1) to afford
the desired
product. 1H NMR (CDC13): 6 7.9 (2H, d, J= 8.8 Hz), 7.12 (2H, d, J = 8.8 Hz),
5.34 (2H, s),
4.2-4.05 (2H, m), 3.03 (3H, s), 3.04-2.85 (3H, m), 2.05-1.96 (2H, m), 1.8-1.7
(2H, m), 1.45
(9H, s).
Example 83
[0444] 4-(5-Benzyloxymethy141,2,4]oxadiazol-3-y1)-piperidine-1-carboxylic acid
tert-butyl
ester
N-0
0 el
0
[0445] To a solution of benzyloxy-acetic acid (5 g, 30 mmol), NEt3 (3.6 g, 36
mmol) in
toluene (150 mL) was added isobutylchloroformate (4.1 g, 30 mmol) at 0 C. The
mixture was
stirred at room temperature for 1.5 hours. 4-(N-hydroxycarbamimidoy1)-
piperidine-1-carboxylic
acid tert-butyl ester (7.3 g, 30 mmol) was added to the mixture. The mixture
was heated under
reflux overnight, cooled and the mixture was washed successively with H20 and
brine. After
drying (Na2SO4), the solvent was removed. The residue was purified by flash
chromatography
on silica gel to afford the desired product. 1EINMR (CDC13): 6 7.4-7.3 (5H,
m), 4.7 (2H, s),
4.69 (2H, s), 4.2-4.04 (2H, m), 3.02-2.84 (3H, m), 2.04-1.94 (2H, m), 1.84-1.7
(2H, m), 1.46
(9H, s).
Example 84
[0446] 5-Ethy1-2-{443-(4-methanesulfonyl-phenoxymethy1)41,2,4]oxadiazol-5-y1]-
piperidin-
1-y1 -pyrimidine
98

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-N
0 _______________________________________________ 0
Th\l/
NN
[0447] To the crude HC1 salt (0.18 g, ¨0.5 mmol) of 443-(4-methanesulfonyl-
phenoxymethy1)41,2,4]oxadiazol-5-y1]-piperidine, prepared by treatment of
44344-
methanesulfonyl-phenoxymethy1)41,2,4]oxadiazol-5-y1]-piperidine-1-carboxylic
acid tert-butyl
ester (Example 81) in dixoane with 4N HC1, was added 2-propanol (3 mL),
followed by DIPEA
(0.13 g, 1 mmol) and 2-Chloro-5-ethyl-pyrimidine (0.14 g, 1 mmol). The
resulting mixture was
stirred at 70 C overnight. After concentration in vacuo, the residue was
purified by silica
column chromatography with Et0Ac/hexanes to afford the desired product. lEINMR
(CDC13):
6 8.18 (2H, s), 7.89 (2H, d, J= 8.8 Hz), 7.15 (2H, d, J= 8.8 Hz), 5.24 (2H,
s), 4.75-4.65 (2H,
m), 3.3-3.2 (1H, m), 3.2-3.1 (2H, m), 3.03 (3H, s), 2.47 (2H, q, J= 7.6 Hz),
2.22-2.16 (2H, m),
1.96-1.84 (2H, m), 1.19 (3H, t, J= 7.6 Hz).
Example 85
[0448] 4-Hydroxy-444-(4-methylsulfanyl-phenoxymethyl)-thiazol-2-y1]-piperidine-
1-
carboxylic acid tert-butyl ester
0 \)
OHN S\
[0449] Step 1: 4-(4-Methylsulfanyl-phenoxymethyl)-thiazole
0 4I
[0450] A mixture of 4-chloromethyl thiazole hydrochloride (3.0 g, 17.6 mmol),
4-
methylsulfanyl-phenol (2.5 g, 1 eq.) and K2CO3 (6.1 g, 2.5 eq.) in acetone (60
mL) was heated
to reflux for 48 hours. After cooling, the solid was filtered off. The
filtrate was evaporated to
dryness in vacuo. The crude product was redissolved in diethyl ether. The
solution was washed
twice with 2N NaOH solution and then with H20. After being dried over Na2SO4,
removal of
the solvent afforded the desired product as an off-white solid.
99

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[0451] Step 2: 4-Hydroxy-444-(4-methylsulfanyl-phenoxymethyl)-thiazol-2-y1]-
piperidine-1-
carboxylic acid tert-butyl ester
0
>\--N
0 OHN \C) S\
[0452] To a stirred solution of 4-(4-methanesulfanyl-phenoxymethyl)-thiazole
(3.92 g, 16.5
mmol) in THF (40 mL) at -78 C was added n-BuLi (1.73 mL, 1.05 eq., 10.0 M in
hexanes).
The resulting solution was stirred at this temperature for 30 minutes. Then a
solution of 1-Boc-
4-piperidone (3.30 g, 1 eq.) in THF (20 mL) was added in dropwise. The
resulting mixture was
stirred for 30 minutes. The reaction was quenched by addition of H20 (5 mL).
Most of the THF
was removed in vacuo. The mixture was extracted with Et0Ac. The organic layer
was
separated, washed with brine and dried over Na2SO4. After removal of the
solvent, the crude
product was purified on silica gel (Et0Ac:hexanes = 2:3) to afford the desired
product as a
foam. 1H NMR (CDC13): 6 7.27 (2H, d, J= 8.8 Hz), 7.26 (1H, s), 6.93 (2H, d, J=
8.8 Hz), 5.14
(2H, s), 4.02 (2H, br), 3.27 (2H, br), 2.97 (1H, br), 2.45 (3H, s), 2.11 (2H,
m), 1.86 (2H, m), 1.48
(9H, s).
Example 86
[0453] 4-Hydroxy-444-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-
piperidine-1-
carboxylic acid tert-butyl ester
0
OH 0 0
S¨

ii
0
[0454] To a solution of 4-hydroxy-4-[4-(4-methylsulfanyl-phenoxymethyl)-
thiazol-2-y1]-
piperidine-1-carboxylic acid tert-butyl ester (Example 85, 6.8 g, 15.6 mmol)
in CH2C12 (150
mL) at room temperature was added m-CPBA (8.4 g, 2.2 eq.) portionwise. The
resulting
solution was stirred for 30 minutes, then it was washed with 2 N NaOH solution
twice and dried
over Na2SO4. After removal of the solvent, the crude product was purified on
silica gel
(Et0Ac:hexanes = 3:2) to afford the desired product as a white foam. lEINMR
(CDC13): 6 7.88
100

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(2H, d, J= 8.8 Hz), 7.31 (1H, s), 7.12 (2H, d, J= 8.8 Hz), 5.24 (2H, s), 4.03
(2H, br), 3.27 (2H,
br), 3.04 (3H, s), 2.13 (2H, m), 1.86 (2H, m), 1.48 (9H, s).
Example 87
[0455] 4-Fluoro-444-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidine-
1-
carboxylic acid tert-butyl ester
0
0 lip
[0456] To a solution of 4-hydroxy-444-(4-methanesulfonyl-phenoxymethyl)-
thiazol-2-y1]-
piperidine-1-carboxylic acid tert-butyl ester (Example 86, 5.29 g, 11.3 mmol)
in CH2C12 (100
mL) at 0 C was added DAST (1.8 mL, 1.2 eq.). The reaction mixture was stirred
for 30
minutes before it was quenched by addition of saturated NaHCO3 solution (20
mL). The
organic phase was separated and dried over Na2SO4. After removal of the
solvent, the crude
product was purified on silica gel (Et0Ac:hexanes = 2:3) to afford the desired
product as a white
solid. 1H NMR (CDC13): 6 7.86 (2H, d, J= 9.2 Hz), 7.35 (1H, s), 7.10 (2H, d,
J= 9.2 Hz), 5.22
(2H, s), 4.08 (2H, br), 3.19 (2H, br), 3.02 (3H, s), 2.05 ¨ 2.32 (4H, m), 1.46
(9H, s).
Example 88
[0457] 5-Ethy1-2-{4-fluoro-444-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-
piperidin-
1-y1 -pyrimidine
S
0 11 FI)
N S----
0
[0458] Step 1: 4-Fluoro-444-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-A-
piperidine
hydrochloride
\\
0
HN HCI
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[0459] To a solution of 4-fluoro-444-(4-methanesulfonyl-phenoxymethyl)-thiazol-
2-y1]-
piperidine-1-carboxylic acid tert-butyl ester (Example 87, 4.24 g, 9.01 mmol)
in methanol (50
mL) was added 4 N HC1 in dioxane (15 mL). The resulting solution was stirred
overnight. The
mixture was then evaporated to dryness in vacuo to afford the desired product
as a white solid.
[0460] Step 2: 5-Ethy1-2-{4-fluoro-444-(4-methanesulfonyl-phenoxymethyl)-
thiazol-2-y1]-
piperidin-l-y1}-pyrimidine
S
=
0
N
0
[0461] A solution of 4-fluoro-444-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-
y1]-
piperidine hydrochloride (4.0 g, 9.01 mmol), 2-chloro-5-ethyl-pyrimidine (1.55
g, 1.2 eq.) and
DIPEA (4.7 g, 4 eq.) in 2-propanol (30 mL) in a sealed pressure vessel was
stirred at 160 C (oil
bath temperature) overnight. After cooling, the solvent was removed in vacuo.
The residue was
partitioned between water and Et0Ac. The organic phase was washed with brine
and dried over
Na2SO4. After removal of the solvent, the crude product was purified on silica
gel
(Et0Ac:hexanes = 1:1) to afford the desired product as a white solid. 1E1 NMIt
(CDC13): 6 8.19
(2H, s), 7.87 (2H, d, J= 9.2 Hz), 7.36 (1H, s), 7.10 (2H, d, J= 9.2 Hz), 5.23
(2H, s), 4.69 (2H,
m), 3.44 (2H, m), 3.03 (3H, s), 2.48 (2H, q, J= 7.6 Hz), 2.15 ¨ 2.39 (4H, m),
1.21 (3H, t, J= 7.6
Hz).
Example 89
[0462] 4-Fluoro-445-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidine-
1-
carboxylic acid tert-butyl ester
/
0
0 410
0
[0463] Step 1: 4-Hydroxy-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-
butyl ester
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0 / N
) 0 _______________________________ N\ _____ ,01-1 S
[0464] To a cooled (-78 C) and stirred solution of n-BuLi (2.6 mL, 1.05 eq.,
10.0 M in
hexanes) in dry Et20 (20 mL) was added dropwise a solution of 2-bromothiazole
(4.0 g, 24.4
mmol) in THF (10 mL) over a 10 minute period. After the yellow mixture had
been stirred at -
78 C for 30 minutes, a solution of 1-Boc-4-piperidone (4.9 g, 1 eq.) in THF
(20 mL) was added
slowly. The mixture was then continued to stir for another 30 minutes before
the reaction was
quenched by addition of water (5 mL). The mixture was warmed to room
temperature and
extracted with Et0Ac. The organic phase was separated, washed with brine and
dried over
Na2SO4. After removal of the solvent, the crude product was purified on silica
gel (45% Et0Ac
in hexanes) to afford the desired product as a thick oil.
[0465] Step 2: 4-Fluoro-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-butyl
ester
0 NI
N
[0466] To a solution of 4-hydroxy-4-thiazol-2-yl-piperidine-1-carboxylic acid
tert-butyl ester
(4.36 g, 15.3 mmol) in CH2C12 (50 mL) at 0 C was added DAST (2.4 mL, 1.2
eq.). The
reaction mixture was stirred for 30 minutes before it was quenched by addition
of saturated
NaHCO3 solution (20 mL). The organic phase was separated and dried over
Na2SO4. After
removal of the solvent, the crude product was purified on silica gel
(Et0Ac:hexanes = 1:4) to
afford the desired product as a pale yellow oil.
[0467] Step 3: 4-Fluoro-4-(5-hydroxymethyl-thiazol-2-y1)-piperidine-1-
carboxylic acid tert-
butyl ester
0 /
N )e--S OH
d
[0468] To a cooled (-78 C) and stirred solution of 4-fluoro-4-thiazol-2-yl-
piperidine-1-
carboxylic acid tert-butyl ester (3.65 g, 12.7 mmol) in THF (20 mL) was added
n-BuLi (1.33
mL, 1.05 eq., 10.0 M in hexanes). The mixture was stirred at this temperature
for 30 minutes.
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Then a suspension of paraformaldehyde (383 mg, 1 eq.) in THF (10 mL) was added
in. The
resulting mixture was continued to stir at -78 C for another 30 minutes and
gradually warmed to
room temperature overnight. The reaction was quenched by addition of water (10
mL). The
mixture was extracted with Et0Ac. The organic phase was washed with brine and
dried over
Na2SO4. After removal of the solvent, the crude product was purified on silica
gel (60% Et0Ac
in hexanes) to afford the desired product as a pale yellow solid.
[0469] Step 4: 4-(5-Chloromethyl-thiazol-2-y1)-4-fluoro-piperidine-1-
carboxylic acid tert-
butyl ester
0 N/ ________________________________ \
S CI
0 \ ____________________________________ F
[0470] To a mixture of 4-fluoro-4-(5-hydroxymethyl-thiazol-2-y1)-piperidine-1-
carboxylic
acid tert-butyl ester (1.34 g, 4.24 mmol) and pyridine (426 mg, 1.3 eq.) in
CH2C12 (30 mL) at 0
C was added MsC1 (631 mg, 1.3 eq.). The mixture was warmed to room temperature
and
stirred overnight. The reaction mixture was washed with saturated NaHCO3
solution and dried
over Na2SO4. Removal of the solvent afforded the desired product, which was
used directly in
the following reaction without further purification.
[0471] Step 5: 4-Fluoro-445-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-
piperidine-1-
carboxylic acid tert-butyl ester
/
o
0 0 110
/I
0
[0472] A mixture of 4-(5-Chloromethyl-thiazol-2-y1)-4-fluoro-piperidine-1-
carboxylic acid
tert-butyl ester (1.42 g, 4.24 mmol), 4-methanesulfonyl-phenol (731 mg, 1.0
eq.) and K2CO3
(878 mg, 1.5 eq.) in acetone (30 mL) was heated to reflux overnight. After
cooling, the solid
was filtered off through a pad of celite. The filtrate was concentrated in
vacuo. The crude
product was purified on silica gel (Et0Ac:hexanes = 1:1) to afford the desired
product as a white
solid. 1H NMIR (CDC13): 6 7.86 (2H, d, J= 9.2 Hz), 7.35 (1H, s), 7.10 (2H, d,
J= 9.2 Hz), 5.22
(2H, s), 4.08 (2H, br), 3.19 (2H, br), 3.02 (3H, s), 2.05 ¨ 2.32 (4H, m), 1.46
(9H, s).
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Example 90
[0473] 5-Ethy1-2-{4-fluoro-445-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-
piperidin-
l-y1 -pyrimidine
\
0 1111
S-
--N
0
[0474] Step 1: 4-Fluoro-445-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-
piperidine
hydrochloride
NI")
S 0
\ 411 9
0 ONH HCI
[0475] To a solution of 4-fluoro-445-(4-methanesulfonyl-phenoxymethyl)-thiazol-
2-y1]-
piperidine-1-carboxylic acid tert-butyl ester (Example 89, 1.30 g, 2.76 mmol)
in methanol (5
mL) was added 4 N HC1 in dioxane (10 mL). The resulting solution was stirred
overnight. The
mixture was then evaporated to dryness in vacuo to afford the desired product
as a white solid.
[0476] Step 2: 5-Ethy1-2-{4-fluoro-445-(4-methanesulfonyl-phenoxymethyl)-
thiazol-2-y1]-
piperidin-1-y1}-pyrimidine
\
0 1111
S-
--N
0
[0477] A solution of 4-fluoro-445-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-
y1]-
piperidine hydrochloride (1.2 g, 2.76 mmol), 2-chloro-5-ethyl-pyrimidine (425
mg, 1.1 eq.) and
DIPEA (1.4 g, 4 eq.) in 2-propanol (20 mL) in a sealed pressure vessel was
stirred at 160 C (oil
bath temperature) overnight. After cooling, the solvent was removed in vacuo.
The residue was
partitioned between water and Et0Ac. The organic phase was washed with brine
and dried over
Na2SO4. After removal of the solvent, the crude product was purified on silica
gel
(Et0Ac:hexanes = 1:1) to afford the desired product as a white solid. 'El NMIt
(CDC13): 6 8.19
(2H, s), 7.90 (2H, d, J= 8.8 Hz), 7.73 (1H, d), 7.10 (2H, d, J= 8.8 Hz), 5.31
(2H, s), 4.67 (2H,
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m), 3.44 (2H, m), 3.04 (3H, s), 2.48 (2H, q, J= 7.6 Hz), 2.13 ¨ 2.38 (4H, m),
1.20 (3H, t, J= 7.6
Hz).
Example 91
[0478] 444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperazine-1-
carboxylic acid
tert-butyl ester
S
r\
0 I. // 0
0
[0479] Step 1: 4-(4-Ethoxycarbonyl-thiazol-2-y1)-piperazine-1-carboxylic acid
tert-butyl ester
0 r"--\
N
N
IYO
[0480] A mixture of 2-bromo-thiazole-4-carboxylic acid ethyl ester (1.4 g,
5.93 mmol),
piperazine-l-carboxylic acid tert-butyl ester (1.16 g, 1.05 eq.) and DIPEA
(1.15 g, 1.5 eq.) in
1,4-dioxane (20 mL) was heated to reflux overnight. After cooling, the solvent
was removed in
vacuo. The crude product was purified on silica gel (Et0Ac:hexanes = 1:4) to
afford the desired
product as a pale yellow solid.
[0481] Step 2: 4-(4-Hydroxymethyl-thiazol-2-y1)-piperazine-1-carboxylic acid
tert-butyl ester
0\\ Nr--\
0H
[0482] A solution of 4-(4-ethoxycarbonyl-thiazol-2-y1)-piperazine-1-carboxylic
acid tert-butyl
ester (1.15 g, 3.37 mmol) in THF (15 mL) at 0 C was treated with LiA1H4 (128
mg, 1 eq.). The
mixture was stirred for 1 hour, then the reaction was quenched with 2 N NaOH
solution. The
solid was filtered off through a pad of celite and washed with Et0Ac (100 mL).
The filtrate was
washed with water and dried over Na2SO4. Removal of the solvent afforded the
desired product
as an oil.
[0483] Step 3: 4-(4-Chloromethyl-thiazol-2-y1)-piperazine-1-carboxylic acid
tert-butyl ester
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NCNN
0
CI
[0484] To a solution of 4-(4-hydroxymethyl-thiazol-2-y1)-piperazine-1-
carboxylic acid tert-
butyl ester (848 mg, 2.83 mmol) and DIPEA (550 mg, 1.5 eq.) in CH2C12 (10 mL)
was added
MsC1 (285 OL, 1.3 eq.) dropwise. The resulting mixture was stirred overnight.
The reaction
solution was then concentrated in vacuo . The crude product was purified on
silica gel
(Et0Ac:hexanes = 1:4) to afford the desired product as an oil.
[0485] Step 4: 444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperazine-
1-
carboxylic acid tert-butyl ester
S
0 r\
0 I. // 0
s,
[0486] A mixture of 4-(4-Chloromethyl-thiazol-2-y1)-piperazine-1-carboxylic
acid tert-butyl
ester (700 mg, 2.20 mmol), 4-methanesulfonyl-phenol (417 mg, 1.1 eq.) and
K2CO3 (609 mg, 2
eq.) in acetone (30 mL) was heated to reflux overnight. After cooling, the
solid was filtered off
through a pad of celite. The filtrate was concentrated in vacuo . The crude
product was purified
on silica gel (Et0Ac:hexanes = 1:1) to afford the desired product as an off-
white solid. 11-1NMR
(CDC13): 6 7.87 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J= 8.8 Hz), 6.59 (1H, s),
5.05 (2H, s), 3.56
(4H, m), 3.48 (4H, m), 3.04 (3H, s), 1.49 (9H, s).
Example 92
[0487] 144-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-4-(2-methyl-propane-
1-
sulfony1)-piperazine
L
0\

\S-N o
0
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[0488] Step 1: 144-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperazine
hydrochloride
0
0 II
HN HCI
[0489] To a solution of 444-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-
piperazine-1-
carboxylic acid tert-butyl ester (Example 91, 430 mg, 0.95 mmol) in methanol
(5 mL) was
added 4 N HC1 in dioxane (5 mL). The resulting solution was stirred for 30
minutes at room
temperature. The mixture was then evaporated to dryness in vacuo to afford the
desired product
as a pale yellow solid.
[0490] Step 2: 144-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-4-(2-methyl-
propane-
1-sulfony1)-piperazine
S
0 N -4N
/0
o,
X\b' S¨

O'
[0491] A solution of 144-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-
piperazine
hydrochloride (100 mg, 0.26 mmol) and DIPEA (134 mL, 3 eq.) in CH2C12 (5 mL)
was added
isobutanesulfonyl chloride (41 mL, 1.2 eq.). The mixture was stirred for 1
hour, then the
reaction solution was directly purified on silica gel (Et0Ac:hexanes = 1:1) to
afford the desired
product as a pale yellow solid. 1H NIVIR (CDC13): 6 7.87 (2H, d, J = 8.8 Hz),
7.12 (2H, d, J =
8.8 Hz), 6.62 (1H, s), 5.05 (2H, s), 3.61 (4H, m), 3.39 (4H, m), 3.04 (3H, s),
2.78 (2H, d, J = 6.8
Hz), 2.32 (1H, m), 1.12 (6H, d, J = 6.8 Hz).
Example 93
[0492] 4[4-Methy1-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic
acid tert-butyl ester
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,N
N "N
s_C-0
0
r
[0493] To a solution of 4-(5-Hydroxymethy1-4-methyl-thiazol-2-y1)-piperidine-1-
carboxylic
acid tert-butyl ester (1.00 g, 3.2 mmol) in THF (6.4 mL) was added, 4-tetrazol-
1-yl-phenol (0.52
g, 3.2 mmol), polymer bound triphenylphosphine (3 mmol/g, 1.6 g). To this
solution was added
ditertierybutylazodicarboxylate (1.1 g, 4.8 mmol), stirred for 4 hours and
filtered through a pad
of celite. The filtrate was concentrated and purified by silica gel
chromatography to provide the
desired product. 1H NMR (CDC13): 6 9.01 (1H, s), 7.66 (2H, d), 7.15 (2H, d),
5.21 (2H, s), 4.19
(2H, m), 3.10 (1H, m), 2.86 (2H, m), 2.45 (3H, s), 2.08 (2H, m), 1.72 (2H, m),
1.47 (9H, s).
Example 94
[0494] 4-{4-[(6-Fluoro-pyridin-3-ylamino)-methyl]-thiazol-2-y1}-piperidine-1-
carboxylic acid
tert-butyl ester
ON
Ni
N F
[0495] 5-amino-2-fluoropyridine (0.476 g, 4.2 mmol) was added to 4-(4-Formyl-
thiazol-2-y1)-
piperidine-1-carboxylic acid tert-butyl ester (0.84 g, 2.8 mmol) in dry DCM
(10 mL). Sodium
triacetoxyborohydride (0.9 g, 4.2 mmol) was then added. The reaction was
stirred for 3 hours at
room temperature under N2. The organic layer was washed with 2 M NaOH
solution, water,
brine, dried (MgSO4), and the solvent was removed in vacuo. The material was
purified by
silica gel chromatography (DCM/methanol: 10:1 v/v) to give the desired
product. 1EINMR
(CDC13): 6 7.59-7.60 (1H, m), 7.06-7.10 (1H, m), 7.02 (1H, s), 6.76 (1H, dd,
J= 8.8, 3,6 Hz),
4.4 (2H, d), 4.20-4.31 (3H, m), 3.09-3.17 (1H, m), 2.8-2.95 (2H, m), 2.07-2.10
(2H, m), 1.77-
1.47, (2H, m), 1.47 (9H, s).
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Example 95
[0496] 1-(3-Isopropy141,2,4]oxadiazol-5-y1)-444-(4-tetrazol-1-yl-
phenoxymethyl)-thiazol-2-
y1]-piperidine
[0497] Step 1: 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carbonitrile
S,
NN ___________________________________ I
-N
N
N
LrI
[0498] To a mixture of 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidine (1.00 g,
2.92 mmol) and potassium carbonate (1.5 g, 10.9 mmol) in chloroform (25 mL)
was added
cyanogen bromide (0.371 g, 3.5 mmol). The slurry was refluxed for 48 hours
then stirred at
room temperature for an additional 48 hours. The reaction was filtered through
a pad of celite,
concentrated and chromatographed on silica gel (1:1 Hexanes/Et0Ac) to afford
the desired
compound.
[0499] Step 2: 1-(3-Isopropy141,2,4]oxadiazol-5-y1)-444-(4-tetrazol-1-yl-
phenoxymethyl)-
thiazol-2-y1]-piperidine
N
N
WC'
[0500] To a solution of 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidine-1-
carbonitrile (0.450, 1.22 mmol) and N-hydroxy-isobutyramidine (0.150 g, 1.47
mmol) in dry
THF (10 mL) was added a 1 M solution of zinc chloride in THF (1.47 mL, 1.47
mmol) over 15
min. The suspension was left to settle for 15 minutes and the white
precipitate was collected by
filtration and dissolved in 4 N HC1 in ethanol and water (1:1). The solution
was refluxed for 1
hour, cooled and the solid precipitate was filtered off The filtrate was
neutralized by the
addition of excess sodium carbonate. The excess was filtered off and the
filtrate was diluted
with Et0Ac. The solution was washed with water, separated, dried (Na2SO4),
filtered and
concentrated. The residual oil was chromatographed on silica gel (1:1
Hex/Et0Ac) to afford the
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desired compound. IIINMR (CDC13): 6 8.92 (1H, s), 7.62 (2H, d), 7.28 (1H, s),
7.19 (2H, d),
5.24 (2H, s), 4.26 (2H, m), 3.20 (3H, m), 2.89 (1H, m), 2.26 (2H, m), 1.92
(2H, m), 1.30 (6H, d).
[0501] The following three examples were synthesized in similar manner as
Example 95
using the required hydroxy amidine and 444-(4-tetrazol-1-yl-phenoxymethyl)-
thiazol-2-y1]-
piperidine-1-carbonitrile.
Example 96
[0502] 1-(3-Ethyl-E1,2,4]oxadiazol-5-y1)-444-(4-tetrazol-1-yl-phenoxymethyl)-
thiazol-2-y1]-
piperidine
0 = =
N
[0503] IIINMR (CDC13): 6 8.85 (1H, s), 7.57 (2H, d), 7.28 (1H, s), 7.19 (2H,
d), 5.17 (2H, s),
4.22 (2H, m), 3.22 (3H, m), 2.55 (2H, q), 2.17 (2H, m), 1.89 (2H, m), 1.35
(3H, t).
Example 97
[0504] 1-(3-Cyclopropy141,2,4]oxadiazol-5-y1)-444-(4-tetrazol-1-yl-
phenoxymethyl)-thiazol-
2-y1]-piperidine
\
N 0 111
N 7
N-C)
[0505] IIINMR (CDC13): 6 8.90 (1H, s), 7.61 (2H, d), 7.27 (1H, s), 7.17 (2H,
d), 5.23 (2H, s),
4.22 (2H, m), 3.22 (3H, m), 2.25 (2H, m), 1.88 (3H, m), 0.96 (4H, m).
Example 98
[0506] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-1-(3-trifluoromethyl-
[1,2,4]oxadiazol-5-y1)-piperidine
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"0 111
N
F N-0
[0507] 111NMR (CDC13): 6 8.92 (1H, s), 7.60 (2H, d), 7.23 (1H, s), 7.16 (2H,
d), 5.21 (2H, s),
4.25 (2H, m), 4.15 (2H, m), 3.22 (1H, m), 2.90 (2H, m), 2.18 (2H, m).
Example 99
[0508] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid amide
[0509] Step 1: 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carbonitrile
S,
NN ___________________________________ I
N¨No
NNs
[0510] To a mixture of 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidine (1.00 g,
2.92 mmol) and potassium carbonate (1.5 g, 10.9 mmol) in chloroform (25 mL)
was added
cyanogen bromide (0.371 g, 3.5 mmol). The slurry was refluxed for 48 hours
then stirred at
room temperature for an additional 48 hours. The reaction was filtered through
a pad of celite,
concentrated and chromatographed on silica gel (1:1 Hexanes/Et0Ac) to afford
the desired
compound.
[0511] Step 2: 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic
acid amide
9,
N
H2N
1\1µ)\1
[0512] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carbonitrile (1.07 g,
2.92 mmol) was dissolved in 4 N HC1 in ethanol/water (1:1). The solution was
refluxed for 1
hour, cooled and the solid precipitate was filtered off The filtrate was
neutralized by the
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addition of excess sodium carbonate. The excess sodium carbonate was filtered
off and the
filtrate was diluted with Et0Ac. The solution was washed with water,
separated, dried
(Na2SO4), filtered and concentrated. The residual oil was chromatographed on
silica gel (1:1
Hexanes/Et0Ac) to afford the desired compound. 1-1-1NMR (CDC13): 6 8.92 (1H,
s), 7.60 (2H,
d), 7.23 (1H, s), 7.167 (2H, d), 5.21 (2H, s), 4.25 (2H, m), 4.15 (2H, m),
3.22 (1H, m), 2.90 (2H,
m), 2.18 (2H, m).
Example 100
[0513] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxamidine
HN
N
H2N
N
[0514] A mixture of 444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidine (300 mg,
0.876 mmol), pyrazole-l-carboxamidine hydrochloride (0.128 g, 0.876 mmol.) and

triethylamine (0.122 mL, 0.876 mmol) in DMF (2 mL) was stirred at rt for 3
hours. The
precipitate was collected by filtration and washed with ether to afford the
expected product. 11-1
NMR (DMSO-d6): 6 10.02 (1H, s), 7.93 (1H, s), 7.82 (2H, m), 7.70 (1H, s),
7.60(2H, br), 7.28
(2H, m), 5.20 (2H, s), 3.95 (2H, m), 3.38 (1H, m), 3.15 (2H, m), 2.09 (2H, m),
1.66 (2H, m).
Example 101
[0515] 344-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-azetidine-1-
carboxylic acid tert-
butyl ester
[0516] Step 1: 3-(4-chloromethyl-thiazol-2-y1)-azetidine-1-carboxylic acid
tert-butyl ester
0 S,
I
N
[0517] To a solution of 3-Thiocarbamoyl-azetidine-1-carboxylic acid tert-butyl
ester (0.800 g,
3.7 mmol) in acetone (15 mL) was added 1,3-dichloroacetone (0.611 g, 4.81
mmol), MgSO4
(0.67 g, 5.6 mmol) and MgCO3 (3.12 g, 3.7 mmol). The mixture was heated under
reflux
overnight, cooled and filtered through celite. The solvent was removed in
vacuo and the residue
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was redissolved with Et0Ac (20 mL). The resulting solution was washed
successively with 5%
NaHS03, saturated NaHCO3, and brine. After drying (Na2SO4), the solvent was
removed to
afford the desired product which was used without further purification.
[0518] Step 2: 344-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-azetidine-1-
carboxylic acid
tert-butyl ester
=N ' N
[0519] A mixture of 3-(4-chloromethyl-thiazol-2-y1)-azetidine-1-carboxylic
acid tert-butyl
ester (From Step 1) (386 mg, 1.34 mmol), 4-tetrazol-1-yl-phenol (217 mg, 1.34
mmol), Cs2CO3
(655 mg, 2.01 mmol) and KI (22 mg, 0.13 mmol) in acetonitrile (5 mL) was
heated under reflux
for 4 hours. After cooling, the solid was filtered through a pad of celite.
The filtrate was
concentrated in vacuo. The residue was purified on silica gel (Et0Ac-hexanes,
1:1) to afford the
desired product. 11-1NMR (CDC13): 6 8.92 (1H, s), 7.61 (2H, d), 7.32 (1H, s),
7.19 (2H, d), 5.25
(2H, s), 4.39 (2H, m), 4.18 (2H, m), 4.14 (1H, m), 1.46 (9H, s).
Example 102
[0520] 3 44-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl] -pyrroli dine-1-
carboxylic acid tert-
butyl ester
O
LN
N-N=
[0521] Step 1: 3-(4-Chloromethyl-thiazol-2-y1)-pyrrolidine-1-carboxylic acid
tert-butyl ester
0
X-)1 N
C I
[0522] To a solution of 3-thiocarbamoyl-pyrrolidine-1-carboxylic acid tert-
butyl ester (1.06 g,
4.60 mmol) in acetone (25 mL) was added 1,3-dichloroacetone (0.76 g, 5.98
mmol), MgSO4
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(0.83 g, 6.1 mmol) and MgCO3 (3.87 g, 4.6 mmol). The mixture was heated under
reflux
overnight, cooled and filtered through celite. The solvent was removed in
vacuo and the residue
was redissolved with Et0Ac (20 mL). The resulting solution was washed
successively with 5%
NaHS03, saturated NaHCO3, and brine. After drying (Na2SO4), the solvent was
removed to
afford the desired product which was used without further purification.
[0523] Step 2: 344-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-pyrrolidine-1-
carboxylic
acid tert-butyl ester
ON-Ns
[0524] A mixture of 3-(4-Chloromethyl-thiazol-2-y1)-pyrrolidine-1-carboxylic
acid tert-butyl
ester (From Step 1) (775 mg, 2.56 mmol), 4-tetrazol-1-yl-phenol (415 mg, 2.56
mmol), Cs2CO3
(1.25 mg, 3.84 mmol) and KI (44 mg, 0.26 mmol) in acetonitrile (20 mL) was
heated under
reflux overnight. After cooling, the solid was filtered through a pad of
celite. The filtrate was
concentrated in vacuo. The residue was purified on silica gel (Et0Ac-hexanes,
1:1) to afford the
desired product. 1H Wit (CDC13): 6 8.92 (1H, s), 7.63 (2H, d), 7.27(1H, s),
7.17 (2H, d), 5.24
(2H, s), 3.87 (1H, m), 3.79 (1H, m), 3.65 (2H, m), 3.45 (1H, m), 2.40 (1H, m),
2.23 (1H, m),
1.47 (9H, s).
Example 103
[0525] 5-Ethy1-2- {344-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
pyrrolidin-1-y1} -
pyrimidine
[0526] Step 1: 1-[4-(2-Pyrrolidin-3-yl-thiazol-4-ylmethoxy)-phenyl]-1H-
tetrazole
HNa_4
N -Ns
LN
[0527] A solution of 344-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
pyrrolidine-1-
carboxylic acid tert-butyl ester (from Example 102) (411 mg, 0.959 mmol) in
dichloromethane
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(10 mL) and methanol (2 mL) were treated with 1 mL of 4 N HC1 in dioxane. The
resulting
solution was stirred at room temperature for 30 minutes. The solvents were
removed in vacuo to
afford the desired product as an HC1 salt.
[0528] Step 2: 5-Ethy1-2-{344-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
pyrrolidin-1-
y1 -pyrimidine
N
tel -N
N=
1\1µj\I
[0529] A mixture of 144-(2-Pyrrolidin-3-yl-thiazol-4-ylmethoxy)-pheny1]-1H-
tetrazole
hydrochloride (From Step 1) (350 mg, 0.959 mmol), 2-chloropyrimidine (0.23 mL,
2.0 eq.) and
K2CO3(398 mg, 2.88 mmol) in DMF (5 mL) was heated at 90 C for 4 hours. Water
was added
and the solution was extracted with ethyl acetate, separated, dried over
sodium sulfate, filtered
and concentrated. The residue was purified on silica gel (50:50 Et0Ac/hexanes)
to afford the
desired product. 1-1-1NMR (CDC13): 6 8.91 (1H, s), 8.21 (2H, s), 7.62 (2H, d),
7.27(1H, s), 7.17
(2H, d), 5.24 (2H, s), 4.12 (1H, m), 3.98 (1H, m), 3.87 (2H, m), 3.69 (1H, m),
2.56 (1H, m), 2.47
(2H, m), 2.37 (1H, m), 1.21 (3H, t).
Example 104
[0530] 344-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid tert-
butyl ester
S,
Nj-NC)
0 -N
N
[0531] Step 1: 3-(4-Chloromethyl-thiazol-2-y1)-piperidine-1-carboxylic acid
tert-butyl ester
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S,
0-(
0
[0532] To a solution of 3-Thiocarbamoyl-piperidine-1-carboxylic acid tert-
butyl ester (2.2 g,
9.02 mmol) in acetone (45 mL) was added 1,3-dichloroacetone (1.49 g, 11.7
mmol), MgSO4
(1.63 g, 13.5 mmol) and MgCO3 (0.76 g, 9.02 mmol). The mixture was heated
under reflux
overnight, cooled and filtered through celite. The solvent was removed in
vacuo and the residue
was redissolved with Et0Ac (20 mL). The resulting solution was washed
successively with 5%
NaHS03, saturated NaHCO3, and brine. After drying (Na2SO4), the solvent was
removed to
afford the desired product which was used without further purification.
[0533] Step 2: 344-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic
acid tert-butyl ester
s,
NjNO
CD
0
'N
[0534] A mixture of 3-(4-Chloromethyl-thiazol-2-y1)-piperidine-1-carboxylic
acid tert-butyl
ester (From Step 1) (300 mg, 0.946 mmol), 4-tetrazol-1-yl-phenol (155 mg,
0.946 mmol),
Cs2CO3 (467 mg, 1.42 mmol) and KI (16 mg, 0.095 mmol) in acetonitrile (10 mL)
was heated
under reflux for 4 hours. After cooling, the solid was filtered through a pad
of celite. The
filtrate was concentrated in vacuo . The residue was purified on silica gel
(Et0Ac-hexanes, 1:1)
to afford the desired product. 1H NMIR (CDC13): 6 8.91 (1H, s), 7.63 (2H, d),
7.26(1H, s), 7.17
(2H, d), 5.24 (2H, s), 4.30 (1H, br), 4.02 (1H, m), 3.20 (1H, m), 3.10 (1H,
br), 2.88 (1H, t),
2.21(1H, m), 1.77 (2H, m), 1.61 (1H, m), 1.47 (9H, s).
Example 105
[0535] 5-Ethy1-2-{344-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
1-y1 -
pyrimidine
[0536] Step 1: 344-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine
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S,
I
HN
N-NõN
[0537] A solution of 344-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidine-1-
carboxylic acid tert-butyl ester (500 mg, 1.13 mmol) in dichloromethane (10
mL) and methanol
(2 mL) were treated with 2 mL of 4 N HC1 in dioxane. The resulting solution
was stirred at
room temperature for 30 minutes. The solvents were removed in vacuo to afford
the desired
product as an HC1 salt.
[0538] Step 2: 5-Ethyl-2- { 3 44-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidin-l-y1 -
pyrimidine
S,
__________________________________ Nj\O
N_(
NN
/IN
4111
[0539] A mixture of 344-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidine
hydrochloride (150 mg, 0.407 mmol), 2-chloropyrimidine (0.074 mL, 2.0 eq.) and
NaHCO3 (171
mg, 2.03 mmol) in DMF (5 mL) was heated at 90 C for 4 hours. Water was added
and the
solution was extracted with ethyl acetate, separated, dried over sodium
sulfate, filtered and
concentrated. The residue was purified on silica gel (50:50 Et0Ac/hexanes) to
afford the
desired product. 1H NMIR (CDC13): 6 8.91 (1H, s), 8.19 (2H, s), 7.63 (2H, m),
7.26(1H, s), 7.17
(2H, m), 5.25 (2H, s), 4.97 (1H, m), 4.62 (1H, m), 3.25 (2H, m), 3.07 (1H, m),
2.46 (2H, q),
2.28(1H, m), 1.88 (2H, m), 1.68 (1H, m), 1.20 (3H, t).
Example 106
[0540] 444-(4-Methanesulfonyl-benzyloxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid
tert-butyl ester
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/:N0
=
,Sr))
> \
C1
[0541] Hydroxybenzy1-4-methylsulfone (1.7 eq.) was dissolved in anhydrous DMF
(10 mL),
cooled to 0 C and NaH (2 eq.) was added in one portion. The reaction was
allowed to stir at 0
C for 30 minutes and at room temperature for an additional 30 minutes. 4-(4-
Chloromethyl-
thiazol-2-y1)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 1)
(0.632 mmol) was
added and the reaction was stirred overnight. The reaction was quenched with
water and
extracted with Et0Ac, dried over sodium sulfate, filtered and concentrated
under reduced
pressure. The residue was purified by silica gel chromatography (Et0Ac/hexanes
1:1) to afford
the desired product. 1H NMR (CDC13): 6 7.92 (2H, d, J= 8.8 Hz ), 7.57 (2H, d,
J= 8.8 Hz),
7.14 (1H, s), 4.71 (2H, s), 4.66 (2H, s), 4.19 (2H, m), 3.13 (1H, m), 3.05
(3H, s), 2.86 (2H, m),
2.09 (2H, m), 1.72 (2H, m), 1.45 (9H, s).
Example 107
[0542] 2-{444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-1-y1 -
pyrimidin-5-
ylamine
N I
I\ON N
N
H2N
[0543] 5-Nitro-2- {444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
1-y1 -
pyrimidine (Example 192) (1.07 mmol), ammonium chloride (3 eq.) and iron
powder (3 eq.)
were suspended in Et0H:THF:H20(40:20:10) and heated at 100 C for 5 hours. The
hot
reaction mixture was filtered through a pad of celite and the filtrate was
concentrated. The
resulting oil was dissolved in DMF and water and extracted with ethylacetate.
The organic layer
was washed with water, brine and dried over sodium sulfate. The resulting
filtrate was
concentrated under reduced pressure. Purification using silica gel
chromatography
(DCM/Me0H 98:2) provided the expected product. 1EINMR (DMSO-d6): 6 9.96 (1H,
s), 7.97
119

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(2H, m), 7.90 (2H, m), 7.63 (1H, s), 5.19 (2H, s), 4.44 (2H, m), 3.73 (1H, m),
2.97 (2H, m), 2.20
(2H, m), 1.95 (2H, m).
Example 108
[0544] N-(2- {444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-l-y1
-pyrimidin-
5-y1)-acetamide
N N(D )N \o /N
r
2N
[0545] 2-{444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-l-y1 -
pyrimidin-5-
ylamine (Example 107) (0.321 mmol) was dissolved in DCM and triethylamine (2
eq.) was
added. The reaction was cooled to 0 C, acetylchloride (1 eq.) was added
dropwise and the
reaction was stirred at room temperature overnight. Water was added and the
mixture was
extracted with ethyl acetate, dried over sodium sulfate, filtered and
concentrated under reduced
pressure. Silica gel chromatography of the resulting oil (DCM/Me0H) provided
the expected
product. 11-INMIR (CDC13): 6 8.84 (1H, s), 8.36 (2H, s), 7.55 (2H, m), 7.19
(1H, s), 7.11 (2H,
m), 6.94 (1H, s), 5.16 (2H, s), 4.77 (2H, m), 3.25 (1H, m), 3.01 (2H, m), 2.16
(2H, m), 2.15 (3H,
s), 1.75 (2H, m).
Example 109
[0546] 444-(4-Tetrazol-1-yl-phenylcarbamoy1)-thiazol-2-y1]-piperidine-1-
carboxylic acid tert-
butyl ester
HN
N N,
N
1\1=N
[0547] 4-(4-Carboxy-thiazol-2-y1)-piperidine-1-carboxylic acid tert-butyl
ester (1.28 mmol)
was dissolved in anhydrous DMF (20mL). To the solution was added triethylamine
(4eq.) and
0-(Benzotriazol-1-y1)-N, N, N', N'-tetramethyluronium tetrafluoroborate (TBTU)
(1.5eq.). The
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reaction was allowed to stir at room temperature for 5 minutes before 4-
tetrazol-1-yl-
phenylamine (1.2 eq.) was added. The reaction was stirred overnight, quenched
with water,
extracted with ethylacetate, washed with brine, dried over sodium sulfate and
filtered. The
organic filtrate was concentrated in vacuo and the residual oil was purified
by column
chromatography (EtOAC/Hex) furnishing the expected product. IIINMR (CDC13): 6
9.37 (1H,
s), 9.02 (1H, s), 8.14 (1H, s), 7.96 (2H, d), 7.72 (2H, d), 4.23 (2H, m), 3.20
(1H, m), 2.91 (2H,
m), 2.14 (2H, m), 1.79 (2H, m), 1.45 (9H, s).
Example 110
[0548] 444-(4-Trifluoromethanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidine-
1-
carboxylic acid tert-butyl ester
0
0
[0549] To a solution of [444-Trifluoromethanesulfanyl-phenoxymethyl)-thiazol-2-
y1]-
piperidine-1-carboxylic acid tert-butyl ester (Example 134) (1.12mmol) in DCM
(20mL) at
room temperature was added 3-chloro-benzenecarboperoxoic acid (2eq.). The
reaction was
allowed to stir for 1.5 hours and an additional portion of 3-chloro-
benzenecarboperoxoic acid (1
eq.) was added to the reaction mixture. The reaction was stirred at room
temperature for an
additional 4 hours. The organic solution was washed with sodium bicarbonate,
the organic layer
was isolated, dried over sodium sulfate and filtered. The filtrate was
concentrated and the crude
product was purified by column chromatography to afford both the expected
sulfone and
sulfoxide products. Sulfone: 1H NMR (DMSO-d6): 6 8.05 (2H, d, J= 8.6 Hz), 7.70
(1H, s),
7.44 (2H, d, J= 8.6 Hz), 5.32 (2H, s), 3.98 (2H, m), 3.19 (1H, m), 2.86 (2H,
m), 2.02 (2H, m),
1.56 (2H, m), 1.38 (9H, s).
Example 111
[0550] 444-(4-Trifluoromethanesulfinyl-phenoxymethyl)-thiazol-2-y1]-piperidine-
1-
carboxylic acid tert-butyl ester
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0
0 =
S-- F
6 F
[0551] This compound was isolated from the reaction mixture of the previous
example. 11-1
NMR (DMSO-d6): 6 8.02 (2H, d, J= 8.6 Hz), 7.75 (1H, s), 7.32 (2H, d, J= 8.6
Hz), 5.31 (2H, s),
3.96 (2H, m), 3.20 (1H, m), 2.85 (2H, m), 2.02 (2H, m), 1.50 (2H, m), 1.38
(9H, s).
[0552] Example 112-145 were synthesized from 4-(4-Chloromethyl-thiazol-2-y1)-
piperidine-
1-carboxylic acid tert-butyl ester (Intermediate 1), 244-(4-Chloromethyl-
thiazol-2-y1)-
piperidin-1-y1]-5-ethyl-pyrimidine (Intermediate 2) or 4-(4-Chloromethyl-
oxazol-2-y1)-
piperidine-1-carboxylic acid tert-butyl ester (Intermediate 14) with the
corresponding phenol,
thiophenol, amine or aniline in a similar manner to that described in Example
1. One skilled in
the art of organic synthesis will appreciate that conditions such as solvent
(such as DMF,
CH3CN); temperature, base (such as NEt3, K2CO3, NaHCO3, Na2CO3, Cs2CO3) and
concentration can be selected through routine experimentation to optimize
yields. Additionally,
alternative coupling methods can be used that are well known in the art of
organic synthesis.
Example 112
[0553] 444-(2,6-Difluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidine-1-
carboxylic acid tert-butyl ester
N 0 N
Oy N N
N N
[0554] 1H NMR (CDC13): 6 8.98 (1H, s), 7.34 (2H, m), 7.30 (1H, s), 5.36 (2H,
s), 4.19 (2H, m),
3.15 (1H, m), 2.87 (2H, m), 2.07 (2H, m), 1.70 (2H, m), 1.47 (9H, s).
Example 113
[0555] 444-(4-Pyrrol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-carboxylic
acid tert-
butyl ester
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N 0 1p
Oy
[0556] 11-1 NIVIR (CDC13): 6 7.24 (3H, m), 7.01 (4H, m), 6.31 (2H, m), 5.17
(2H, s), 4.21 (2H,
m), 3.14 (1H, m), 2.87 (2H, m), 2.01 (2H, m), 1.74 (2H, m), 1.47 (9H, s).
Example 114
[0557] 4-{4-[(4-Tetrazol-1-yl-phenylamino)-methyl]-thiazol-2-y1}-piperidine-1-
carboxylic
acid tert-butyl ester
H\N ,m
7
oyN
[0558] 1-HNIVIR (CDC13): 6 8.85 (1H, s), 7.40 (2H, m), 7.01 (1H, s), 6.72 (2H,
m), 4.76 (1H, s),
4.44 (2H, s), 4.15 (2H, m), 3.08 (1H, m), 2.83 (2H, m), 2.04 (2H, m), 1.66
(2H, m), 1.43 (9H, s).
Example 115
[0559] 2-{444-(3-Chloro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
1-y1}-5-
ethyl-pyrimidine
CI
N 0 /N
N
N N
N--=N
[0560] 1-HNIVIR (CDC13): 6 8.93 (1H, s), 8.18 (2H, s), 7.48 (1H, m), 7.25 (1H,
s), 7.08 (2H, m),
5.22 (2H, s), 4.82 (2H, m), 3.29 (1H, m), 3.04 (2H, m), 2.46 (2H, q), 2.21
(2H, m), 1.80 (2H, m),
1.18 (3H, t).
Example 116
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[0561] N-(4-{241-(5-Ethyl-pyrimidin-2-y1)-piperidin-4-y1]-thiazol-4-ylmethoxy}-
pheny1)-
formamide
\/
0 geoN
[0562] 1-H NMR (CDC13): 6 8.55-8.30 (1H, m), 8.18 (2H, s), 7.50-6.90 (6H,
m), 5.14 (2H, s),
4.83 (2H, m), 3.29 (1H, m), 3.03 (2H, m), 2.46 (2H, q), 2.20 (2H, m), 1.80
(2H, m), 1.19 (3H, t).
Example 117
[0563] N-(4-{241-(5-Ethyl-pyrimidin-2-y1)-piperidin-4-y1]-thiazol-4-ylmethoxy}-
pheny1)-
methanesulfonamide
rL
0 IF
NH
;S=0
\
[0564] 1-14 NMR (CDC13): 6 8.20 (s, 2H), 7.21 (m, 3H), 6.95 (m, 2H), 5.13 (s,
2H), 4.81 (m,
2H), 3.29 (m, 1H), 3.06 (m, 2H), 2.94 (s, 3H), 2.47 (q, 2H), 2.20 (m, 2H),
1.81 (m, 2H), 1.19 (t,
3H).
Example 118
[0565] 444-(2-Methy1-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic
acid tert-butyl ester
rLN 0
0 N, N
[0566] 1-14NMR (CDC13): 6 8.89 (1H, s), 7.48 (1H, s), 7.43 (1H, m), 7.25 (1H,
m), 7.05 (1H,
m), 5.27 (2H, s), 4.27 (2H, m), 3.18 (1H, m), 2.89 (2H, m), 2.37 (3H, s), 2.21
(2H, m), 1.74 (2H,
m), 1.47 (9H, s).
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Example 119
[0567] 5-Ethy1-2-{444-(4-tetrazol-1-y1-2-trifluoromethyl-phenoxymethyl)-
thiazol-2-y1]-
piperidin-l-y1}-pyrimidine
0 = N/N
NyN
NN
I I F3C
[0568] 1-14 NMR (CDC13): 6 8.97 (1H, s), 8.18 (2H, s), 7.92 (1H, m), 7.84
(1H, m), 7.33 (1H,
m), 7.26 (1H, s), 5.38 (2H, s), 4.81 (2H, m), 3.27 (1H, m), 3.05 (2H, m), 2.46
(2H, q), 2.19 (2H,
m), 1.79 (2H, m), 1.19 (3H, t).
Example 120
[0569] 2-{444-(2-Chloro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
l-y1}-5-
ethyl-pyrimidine
0 /N
N
NyNNN
CI
[0570] lEINMR (acetone-d6), 6 9.68 (1H, s), 8.24 (2H, s), 8.01 (1H, s), 7.86
(1H, m), 7.60 (1H,
m), 7.59 (1H, s), 5.40 (2H, s), 4.82 (2H, m), 3.36 (1H, m), 3.08 (2H, m), 2.48
(2H, q), 2.17 (2H,
m), 1.75 (2H, m), 1.18 (3H, t).
Example 121
[0571] 444-(4-Tetrazol-1-yl-phenoxymethyl)-oxazol-2-y1]-piperidine-1-
carboxylic acid tert-
butyl ester
r-LN 0 /N
ON NN
125

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[0572] 1H NIVIR (CDC13): 6 8.94 (1H, s), 7.65 (1H, s), 7.60 (2H, m), 7.13 (2H,
m), 5.01 (2H, s),
4.08 (2H, m), 2.94 (3H, m), 2.03 (2H, m), 1.75 (2H, m), 1.43 (9H, s).
Example 122
[0573] 444-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-oxazol-2-y1]-piperidine-1-
carboxylic
acid tert-butyl ester
0 1110+ /N
N
NN
ON
[0574] 1HNMR (CDC13): 6 8.88 (1H, s), 7.62 (1H, s), 7.45 (1H, m), 7.36 (1H,
m), 7.23 (1H,
m), 5.05 (2H, s), 4.04 (2H, m), 2.85 (3H, m), 1.97 (2H, m), 1.71 (2H, m), 1.40
(9H, s).
Example 123
[0575] 5-Ethy1-2-{444-(4-methanesulfonyl-phenoxymethyl)-oxazol-2-y1]-piperidin-
l-y1} -
pyrimidine
CH
rL
0 = NyN
[0576] 1H NMR (CDC13): 6 8.16 (2H, s), 7.84 (2H, m), 7.63 (1H, s), 7.08 (2H,
m), 5.02 (2H, s),
4.67 (2H, m), 3.08 (3H, m), 3.01 (3H, s), 2.44 (2H, q), 2.12 (2H, m), 1.84
(2H, m), 1.17 (3H, t).
Example 124
[0577] 444-(2,6-Difluoro-4-propionyl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic
acid tert-butyl ester
126

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o SNN

fa_4-LO
0
[0578] 1H Wit (CDC13): 6 7.51 (2H, d), 7.27 (1H, s), 5.37 (2H, s), 4.18 (2H,
m), 3.14 (1H,
m), 2.92 (2H, q, J= 7.4 Hz), 2.88 (2H, m), 2.07 (2H, m), 1.71 (2H, m), 1.47
(9H, s), 1.21 (3H, t,
J = 7.4 Hz).
Example 125
[0579] 444-(4-Acety1-2-fluoro-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid
tert-butyl ester
410
0 N1N

Me
0
[0580] 1H Wit (CDC13): 6 7.70-7.72 (2H, m), 7.28 (1H, s), 7.09-7.13 (1H, m),
5.30 (2H, s),
4.20 (2H, m), 3.17 (1H, m), 2.88 (2H, m), 2.55 (3H, s), 2.10 (2H, m), 1.72
(2H, m), 1.47 (9H, s).
Example 126
[0581] 444-(4-Cyano-2-fluoro-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid
tert-butyl ester
00,..4-LO
CN
[0582] 1H Wit (CDC13): 6 7.37-7.42 (2H, m), 7.27 (1H, s), 7.137.17(1H, m),
5.28 (2H, s),
4.20 (2H, m), 3.15 (1H, m), 2.89 (2H, m), 2.09 (2H, m), 1.72 (2H, m), 1.47
(9H, s).
Example 127
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[0583] 4-[4-(6-Tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic
acid tert-butyl ester
I N
¨N
[0584] IIINMR (CDC13): 6 9.41 (1H, s), 8.27 (1H, d), 8.01 (1H, d,), 7.58 (1H,
dd,), 7.28 (1H,
s), 5.27 (2H, s), 4.20 (2H, m), 3.14-3.20 (1H, m), 2.87 (2H, m), 2.09-2.12
(2H, m), 1.68-1.78
(2H, m), 1.46 (9H, s)
Example 128
[0585] 4-[4-(4-[1,2,3]Triazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid
tert-butyl ester
0 N 0
N.
>101
[0586] IIINMR (CDC13): 6 7.92 (1H, s), 7.84 (1H, s), 7.65 (2H, d), 7.25 (1H,
s), 7.11 (2H, d),
5.22 (2H, s), 4.21 (2H, br), 3.18 (1H, m), 2.88 (2H, br), 2.12 (2H, m), 1.75
(2H, m), 1.47 (9H, s).
Example 129
[0587] 444-(4-Ethoxycarbonyl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid
tert-butyl ester
0
Oy N
>0
128

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[0588] IIINMR (CDC13): 6 8.01 (2H, d), 7.23 (1H, s), 7.01 (2H, d), 5.22 (2H,
s), 4.36 (2H,
q), 4.22 (2H, br), 3.17 (1H, m), 2.87 (2H, br), 2.12 (2H, m), 1.75 (2H, m),
1.47 (9H, s), 1.39
(2H, t).
Example 130
[0589] 444-(4-tert-Butoxycarbonylamino-phenoxymethyl)-thiazol-2-y1]-piperidine-
1-
carboxylic acid tert-butyl ester
'NH
oy N
0
>0
[0590] IIINMR (CDC13): 6 7.28 (2H, d), 7.19 (1H, s), 6.92 (2H, d), 6.40 (1H,
s), 5.12 (2H, s),
4.22 (2H, br), 3.17 (1H, m), 2.87 (2H, br), 2.12 (2H, m), 1.75 (2H, m), 1.50
(9H, s), 1.47 (9H, s).
Example 131
[0591] 444-(4-Carboxy-phenoxymethyl)-thiazol-2-y1]-piperidine-1-carboxylic
acid tert-butyl
ester
3,z0
0
Oy N
OH
>0
[0592] 1H NMR (DMSO-d6): 6 7.86 (2H, d), 7.64(1H, s), 7.10 (2H, d), 5.17 (2H,
s), 3.96
(2H, m), 3.18 (1H, m), 2.87 (2H, br), 1.96 (2H, m), 1.49 (2H, m), 1.38 (9H,
s).
Example 132
[0593] 444-(2,6-Difluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-
piperidine-1-
carboxylic acid tert-butyl ester
129

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3/0
0 N 0
>0
[0594] 1H NMR (CDC13): 6 7.42(2H, d), 7.21 (1H, s), 5.25 (2H, s), 4.12 (2H,
br), 3.17(1H,
m), 3.00 (3H, s), 2.87 (2H, br), 1.98 (2H, m), 1.71 (2H, m).
Example 133
[0595] 444-(4-Morpholin-4-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid
tert-butyl ester
0,
N _____ I
7-0 \
NTh
c0
[0596] 1H NMR (CDC13): 6 7.19(1H, s), 6.92 (4H, m), 5.12(2H, s), 4.20 (2H,
br), 3.85 (4H,
br), 3.16 (1H, m), 3.07 (4H, m), 2.86 (2H, m), 2.10 (2H, m), 1.72 (2H, m),
1.47 (9H, s).
Example 134
[0597] 444-(4-Trifluoromethylsulfanyl-phenoxymethyl)-thiazol-2-y1]-piperidine-
1-carboxylic
acid tert-butyl ester
S
o
0
s
C F3
[0598] 1EINMR (DMSO-d6): 6 7.64 (1H, s), 7.63 (2H, d, J = 8.6 Hz), 7.17 (2H,
d, J = 8.6 Hz),
5.17 (2H, s), 3.99 (2H, m), 3.18 (1H, m), 2.83 (2H, m), 2.01 (2H, m), 1.52
(2H, m), 1.38 (9H, s).
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Example 135
[0599] 444-(4-Benzyloxy-phenoxymethyl)-thiazol-2-y1]-piperidine-1-carboxylic
acid tert-
butyl ester
0
0
1.1 0O
[0600] 1H Wit (DMSO-d6): 6 7.55 (1H, s), 7.41 (5H, m), 6.92 (4H, m), 5.12 (4H,
s), 3.98
(2H, m), 3.20 (1H, m), 2.84 (2H, m), 2.01 (2H, m), 1.52 (2H, m), 1.38 (9H, s).
Example 136
[0601] 444-(2-Acetylamino-4-methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-
piperidine-1-
carboxylic acid tert-butyl ester
0
)0 0 N 0
H3C)L11 0
[0602] 1H Wit (CDC13): 6 8.81 (1H, s), 7.97 (1H, s), 7.53 (1H, d), 7.25 (1H,
s), 7.09 (1H, d),
5.24 (2H, s), 4.16 (2H, m), 3.10 (3H, m), 2.83 (2H, m), 2.16 (3H, s), 2.04
(2H, d), 1.66 (2H, m),
1.40 (9H, s), 1.19(3H, t).
Example 137
[0603] 4-(4-Phenoxymethyl-thiazol-2-y1)-piperidine-1-carboxylic acid tert-
butyl ester
oy
O NN
[0604] 1H NIVIR (CDC13): 6 7.28 (2H, m), 7.19 (1H, s), 6.93 (3H, m), 5.14 (2H,
s), 4.19 (2H, s),
3.15 (1H, m), 2.85 (2H, m), 2.07 (2H, d), 1.67 (2H, m), 1.45 (9H, s).
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Example 138
[0605] 4-{4-[(4-Methanesulfonyl-phenylamino)-methy1]-thiazol-2-y1} -piperidine-
1-carboxylic
acid tert-butyl ester
0
(Dz
HN
0
Oy N
[0606] 1-14 NMR (CDC13): 6 7.67 (2H, d, J= 8.8 Hz), 6.99 (1H, s), 6.67 (2H, d,
J = 8.8 Hz),
5.07 (1H, m), 4.45 (2H, d), 4.18 (2H, s), 3.13 (1H, m), 2.97 (3H, s), 2.85
(2H, m), 2.04 (2H, d),
1.68 (2H, m), 1.44 (9H, s).
Example 139
[0607] 4-{4-[(2-Fluoro-4-methanesulfonyl-phenylamino)-methy1]-thiazol-2-y1} -
piperidine-1-
carboxylic acid isopropyl ester
F
Ov
HN
0
/IW
0/
[0608] 1-14 NMR (CDC13): 6 7.55 (2H, m), 7.05 (1H, s), 6.76 (1H, m), 5.12 (1H,
m), 4.52 (2H,
d), 4.19 (2H, m), 3.13 (1H, m), 3.05 (3H, s), 2.86 (2H, m), 2.10 (2H, m), 1.76
(2H, m), 1.46 (9H,
s).
Example 140
[0609] 444-(4-Bromo-phenoxymethyl)-thiazol-2-y1]-piperidine-1-carboxylic acid
tert-butyl
ester
O SNN
0
Br
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[0610] 11-1NMR (CDC13): 6 7.36 (2H, m), 7.17 (1H, s), 6.82 (2H, m), 5.10 (2H,
s), 4.18 (2H, s),
3.13 (1H, m), 2.85 (2H, m), 2.09 (2H, d), 1.75 (2H, m), 1.43 (9H, s).
Example 141
[0611] {241-(5-Ethyl-pyrimidin-2-y1)-piperidin-4-y1]-thiazol-4-ylmethyl -(2-
fluoro-4-
methanesulfonyl-pheny1)-amine
0
N HN Sll¨

N N
[0612] 1-14 NMR (CDC13): 6 8.16 (2H, s), 7.52 (2H, m), 7.01 (1H, s), 6.74 (1H,
m), 5.15 (1H,
m), 4.83 (2H, m), 4.51 (2H, d), 3.26 (1H, m), 3.02 (5H, m), 2.46 (2H, m), 2.19
(2H, m), 1.78
(2H, m), 1.19 (3H, t).
Example 142
[0613] 4-{4-[(4-Methanesulfonyl-benzylamino)-methy1]-thiazol-2-y1} -piperidine-
1-carboxylic
acid tert-butyl ester
R CH
\Sµ' 3
=µ0
) 0
[0614] 1-14 NMR (CDC13): 6 7.85 (2H, d, J= 8.8 Hz), 7.53 (2H, d, J = 8.8 Hz),
6.95 (1H, s),
4.14 (2H, s), 3.87 (2H, s), 3.83 (2H, s), 3.11 (1H, m), 3.04 (3H, s), 2.86
(2H, m), 2.07 (3H, m),
1.67 (2H, m), 1.42 (9H, s).
Example 143
[0615] 4444 [1-(4-Methanesulfonyl-phenyl)-ethylamino]-methyl -thiazol-2-y1)-
piperidine-1-
carboxylic acid tert-butyl ester
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(D\
N
\SCI-13
H \\O
) 0
oH3
[0616] 111 NMR (CDC13): 6 7.87 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz),
6.87 (1H, s),
4.22 (2H, m), 3.90 (1H, s), 3.66 (2H, m), 3.09 (1H, m), 3.04 (3H, s), 2.82
(3H, m), 2.02 (2H, m),
1.71 (2H, m), 1.40 (9H, s), 1.29 (3H, d).
Example 144
[0617] 3-Methy1-444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic
acid tert-butyl ester
N N
µN=N
[0618] 1H NMR (CDC13): 6 8.93 (1H, s), 7.61 (2H, m), 7.25 (1H, m), 7.12 (2H,
m), 5.22 (2H,
m), 4.2 (1H, m), 3.95 (1H, m), 3.33 (1H, m), 3.13 (1H, m), 2.8 (1H, m), 2.34
(1H, m), 2.04 (1H,
m), 1.89 (1H, m), 1.45 (9H, s), 0.85 (3H, m).
Example 145
[0619] 444-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-3-methyl-
piperidine-1-
carboxylic acid tert-butyl ester
NN
0 II i\i/N
0 N
y
[0620] 1H NMR (CDC13): 6 9.07(1H, s), 7.51 (1H, m), 7.41 (1H, m), 7.23 (2H,
m), 5.25 (2H,
s), 4.16 (1H,m), 3.88 (1H, m), 3.34 (1H, m), 3.09 (1H, m), 2.8 (1H, m), 2.26
(1H, m), 1.96 (1H,
m), 1.83 (1H, m), 1.39 (9H, s), 0.76 (3H, m).
[0621] Examples 146-157 were synthesized from one of Intermediates 3-13 or
Intermediates 15-25 with the corresponding sulfonyl chloride, alkyl chloride,
alkyl bromide,
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chloroformate, acid chloride, carbamyl chloride or isocyanate in a manner
similar to that
described in Example 22. One skilled in the art of organic synthesis will
appreciate that
conditions such as solvent (e.g., DMF, CH3CN); temperature, base (e.g., NEt3,
K2CO3, NaHCO3,
Na2CO3, Cs2CO3) and concentration can be selected through routine
experimentation to
optimize yields. Additionally, alternative coupling methods can be used that
are well known in
the art of organic synthesis.
Example 146
[0622] 444-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic
acid allyl ester
S\
/N
OyN
l\F=N
0
[0623] 1HNMR (CDC13), 6 9.00 (1H, s), 7.54 (1H, m), 7.45 (1H, m), 7.29 (2H,
m), 5.95 (1H,
m), 5.30 (3H, m), 5.22 (1H, m), 4.61 (2H, m), 4.28 (2H, m), 3.20 (1H, m), 2.98
(2H, m), 2.14
(2H, m), 1.78 (2H, m).
Example 147
[0624] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid
cyclohexyl ester
OyN
[0625] 1H NMR (CDC13): 6 8.91 (1H, s), 7.60 (2H, m), 7.25 (1H, s), 7.16 (2H,
m), 5.22 (2H, s),
4.68 (1H, m), 4.36 (2H, m), 3.19 (1H, m), 2.91 (2H, m), 2.12 (2H, m), 1.88
(6H, m), 1.40 (6H,
m).
Example 148
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[0626] 444-(2-Fluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-y1]-piperidine-
1-
carboxylic acid isopropyl ester
0.....-NOSI\-1 P
e
\ro
[0627] IIINMR (CDC13): 6 7.64-7.70 (2H, m), 7.20-7.26 (2H, m), 5.29 (2H, s),
4.89-4.95
(1H, m), 4.24 (2H, m), 3.13-3.19 (1H, m), 3.03 (3H, s), 2.86-2.93 (2H, m),
2.11 (2H, m),
1.69-1.78 (2H, m), 1.23 (6H, d, J= 6.4 Hz).
Example 149
[0628] 1-Isopropy1-444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidine
N¨LO
)..-Nra(N 410
MN
h1=1\1
[0629] IIINMR (DMSO-d6): 6 9.98 (1H, s), 7.79 (2H, d, J= 8.8 Hz), 7.63 (1H,
s), 7.28 (2H,
d, J = 8.8 Hz), 5.19 (2H, s), 2.91 (1H, m), 2.82 (2H, m), 2.68 (1H, m), 2.20
(2H, m), 2.01 (2H,
m), 1.63 (2H, m), 0.94 (6H, d, J= 6.4 Hz).
Example 150
[0630] 1-Propy1-444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine
410 N N
h141
[0631] IIINMR (DMSO-d6): 6 9.97 (1H, s), 7.80 (2H, d, J= 8.8 Hz), 7.64 (1H,
s), 7.28 (2H,
d, J = 8.8 Hz), 5.20 (2H, s), 2.94 (1H, m), 2.88 (2H, m), 2.22 (2H, t, J= 7.2
Hz), 1.99 (4H, m),
1.64 (2H, m), 1.41 (2H, m), 0.83 (3H, t, J= 7.2 Hz).
Example 151
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[0632] 3,3 -Dimethyl-1- {444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-A-
piperidin-l-y1 -
butan-2-one
NrN
1\1=KI
[0633] IIINMR (DMSO-d6): 6 9.98 (1H, s), 7.80 (2H, d, J= 8.8 Hz), 7.64 (1H,
s), 7.28 (2H,
d, J = 8.8 Hz), 5.20 (2H, s), 3.41 (2H, s), 2.95 (1H, m), 2.82 (2H, m), 2.18
(2H, m), 1.98 (2H,
m), 1.69 (2H, m), 1.07 (9H, s).
Example 152
[0634] 1-Butyl-444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine
a____CLO =
µN=1\1
[0635] IIINMR (DMSO-d6): 6 9.97 (1H, s), 7.80 (2H, d, J= 8.8 Hz), 7.64 (1H,
s), 7.28 (2H,
d, J = 8.8 Hz), 5.20 (2H, s), 2.94 (1H, m), 2.88 (2H, m), 2.26 (2H, t, J= 6.8
Hz), 1.98 (4H, m),
1.66 (2H, m), 1.39 (2H, m), 1.26 (2H, m), 0.86 (3H, t, J= 7.2 Hz).
Example 153
[0636] 2-{444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-l-y1 -1-
(4-
trifluoromethoxy-pheny1)-ethanone
I.D___41,_/0 =
NrN
µ1\1=1\1
0
F3C0
[0637] 1H NMR (DMSO-d6): 6 9.97 (1H, s), 8.14 (2H, d, J= 6.4 Hz), 8.02 (2H, d,
J = 6.4 Hz),
7.80 (2H, d, J = 8.8 Hz), 7.64 (1H, s), 7.28 (2H, d, J = 8.8 Hz), 5.20 (2H,
s), 3.84 (2H, s), 2.98
(1H, m), 2.93 (2H, m), 2.38 (2H, m), 2.00 (2H, m), 1.68 (2H, m).
Example 154
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[0638] 1-Methanesulfony1-444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidine
0si
II \ N
0 ___________________________
N
N '
¨N
[0639] 1H NMR (DMSO-d6): 6 9.98 (1H, s), 7.81 (2H, d, J= 8.8 Hz), 7.69 (1H,
s), 7.29 (2H, d,
J= 8.8 Hz), 5.21 (2H, s), 3.60-3.63 (2H, m), 3.32 (3H, s), 3.12-3.18 (1H, m),
2.83-2.90 (2H, m),
2.14-2.17 (2H, m), 1.71 (2H, m).
Example 155
[0640] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid heptyl
ester
OyN 0 = ,N
N
0
[0641] IIINMR (CDC13): 6 8.91 (1H, s), 7.60 (2H, d), 7.25 (1H, s), 7.19 (2H,
d), 5.24 (2H, s),
4.26 (2H, br), 4.09 (2H, t), 3.20 (1H, m), 2.94 (2H, m), 2.16 (2H, m), 1.77
(2H, m), 1.60 (2H,
m), 1.32 (8H, m), 0.90 (3H, t).
Example 156
[0642] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-1-(toluene-4-
sulfony1)-piperidine
S
0 N 0 lip
\\s,N
\O
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[0643] 111 NMR (CDC13): 6 8.91 (1H, s), 7.67 (2H, d, J= 8.8 Hz), 7.59 (2H, d,
J= 8.8 Hz),
7.35 (2H, d, J= 8.8 Hz), 7.25 (1H, s), 7.15 (2H, m), 5.19 (2H, s), 3.91 (2H,
d), 2.95 (1H, m),
2.44 (3H, s), 2.37 (2H, m), 2.17 (2H, d), 1.94 (2H, m).
Example 157
[0644] 2-tert-Butoxy-1-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidin-l-y1 -
ethanone
\c) 111
N
[0645] 1H NMR (DMSO-d6): 6 9.99 (1H, s), 7.81 (2H, m), 7.26 (2H, m), 5.20 (2H,
s), 4.36
(1H, m), 3.97 (3H, m), 3.28 (1H, m), 3.12 (1H, m), 2.71 (1H, m), 2.04 (2H, m),
1.67 (1H, m),
1.46(1H, m), 1.13(9H, s).
[0646] Examples 158-205 were synthesized from one of Intermediates 3-13 or
Intermediates 15-25 with the corresponding 2-chloropyrimidine, 2-
iodopyrimidine, 2-
chloropyridine, 2-fluoropyridine, 2-methanesulfonyl-pyrimidine, 2-
chloropyrazine, 2-
chloropyridazine or other suitable heterocycles in a manner similar to that
described in Example
47. One skilled in the art of organic synthesis will appreciate that
conditions such as solvent
(such as DMF, CH3CN); temperature, base (such as NEt3, K2CO3, NaHCO3, Na2CO3,
Cs2CO3)
and concentration can be selected through routine experimentation to optimize
yields.
Additionally, alternative coupling methods can be used that are well known in
the art of organic
synthesis.
Example 158
[0647] 5-Ethy1-2-{444-(3-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidin-1-
y1 -pyrimidine
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N
fNyN
[0648] 1H NIVIR (CDC13): 6 9.04 (1H, s), 8.19 (2H, s), 7.78 (1H, m), 7.28 (1H,
s), 6.70 (2H, m),
5.23 (2H, s), 4.83 (2H, m), 3.31 (1H, m), 3.05 (2H, m), 2.47 (2H, q), 2.21
(2H, m), 1.81 (2H, m),
1.20 (3H, t).
Example 159
[0649] 2-{444-(2,6-Difluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidin-l-y1}-5-
ethyl-pyrimidine
rN1/
N
NN
[0650] 1H Wit (CDC13): 6 8.95 (1H, s), 8.17 (2H, s), 7.34 (2H, m), 7.28 (1H,
s), 5.35 (2H, s),
4.76 (2H, m), 3.27 (1H, m), 3.04 (2H, m), 2.46 (2H, q), 2.16 (2H, m), 1.76
(2H, m), 1.19 (3H, t).
Example 160
[0651] 5-Ethy1-2-{444-(4-pyrrol-1-yl-phenoxymethyl)-thiazol-2-A-piperidin-l-
y1}-
pyrimidine
N 0 111
I
[0652] 1H Wit (CDC13): 6 8.18 (2H, s), 7.29(2H, m), 7.20(1H, s), 6.99(4H, m),
6.31 (2H,
m), 5.17 (2H, s), 4.84 (2H, m), 3.28 (1H, m), 3.03 (2H, m), 2.46 (2H, q), 2.21
(2H, m), 1.81 (2H,
m), 1.19 ( 3H, t).
Example 161
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[0653] {2-[1-(5-Ethyl-pyrimidin-2-y1)-piperidin-4-y1]-thiazol-4-ylmethy1}-
(4-tetrazol-1-y1-
phenyl)-amine
S
N HN /to N
N
N'N
I
\N
[0654] 1-HNIVIR (CDC13): 6 8.83 (1H, s), 8.16 (2H, s), 7.41 (2H, m), 7.02 (1H,
s), 6.74 (2H, m),
4.82 (1H, s), 4.79 2H, s), 4.45 (2H, m), 3.25 (1H, m), 3.01 (2H, m), 2.44 (2H,
q), 2.17 (2H, m),
1.77 (2H, m), 1.11 (3H, t).
Example 162
[0655] 2-{444-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
l-y1}-5-
isopropyl-pyrimidine
1100
iNYN N,
N'N
[0656] 1-HNIVIR (CDC13): 6 8.92 (1H, s), 8.21 (2H, s), 7.51 (1H, m), 7.40 (1H,
m), 7.29 (1H, s),
7.26 (1H, m), 5.30 (2H, s), 4.82 (2H, m), 3.28 (1H, m), 3.04 (2H, m), 2.77
(1H, m), 2.20 (2H, m),
1.80 (2H, m), 1.23 (6H, d).
Example 163
N 0 11N N N
N'N
y
OH
[0657] 1-HNIVIR (CDC13): 6 8.97 (1H, s), 7.80 (1H, s), 7.50 (1H, m), 7.40 (1H,
m), 7.27 (1H, s),
7.24 (1H, m), 5.27 (2H, s), 4.42 (4H, m), 3.24 (1H, m), 3.04 (9H, m), 2.16
(2H, m), 1.88 (2H, m).
Example 164
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[0658] 5-Ethy1-2-{444-(2-methy1-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidin-1-
y1}-pyrimidine
S
N
N
[0659] 1-HNIVIR (CDC13): 6 8.88 (1H, s), 8.19 (2H, s), 7.48 (1H, s), 7.44 (1H,
m), 7.24 (1H, m),
7.05 (1H, m), 5.26 (2H, s), 4.83 (2H, m), 3.27 (1H, m), 3.05 (2H, m), 2.47
(2H, q), 2.37 (3H, s),
2.22 (2H, m), 1.81 (2H, m), 1.19 (3H, t).
Example 165
[0660] 5-Chloro-2-{444-(2-chloro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidin-1-
y1}-pyrimidine
r-LN 0 /N
'NN
iNYN
CI
CI
[0661] 1-HNIVIR (acetone-d6), 6 9.68 (1H, s), 8.33 (2H, s), 8.01 (1H, s), 7.86
(1H, m), 7.60 (1H,
m), 7.59 (1H, s), 5.40 (2H, s), 4.78 (2H, m), 3.40 (1H, m), 3.16 (2H, m), 2.20
(2H, m), 1.77 (2H,
m).
Example 166
[0662] 2-{444-(2-Chloro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
1-y1}-5-
trifluoromethyl-pyrimidine
\0
'NN
iNYN
CI
F3CN
142

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[0663] 1H NMR (acetone-d6), 6 9.68 (1H, s), 8.62 (2H, s), 8.01 (1H, s), 7.86
(1H, m), 7.61 (1H,
s), 7.60 (1H, m), 5.41 (2H, s), 4.92 (2H, m), 3.46 (1H, m), 3.27 (2H, m), 2.25
(2H, m), 1.80 (2H,
m).
Example 167
[0664] 2-{ 444-(2-Isopropy1-5-methy1-4-tetrazol-1-y1 -phenoxymethyl)-thiazol-2-
yl] -piperidin-
1-y1 } -5-trifluoromethyl-pyrimi dine
S
(yN 0
F3C ----N N zN
N=KI
[0665] 1H NMR (CDC13): 6 8.73 (1H, s), 8.46 (2H, s), 7.22 (1H, s), 7.10 (1H,
s), 6.90 (1H, s),
5.24 (2H, s), 4.93 (2H, m), 3.35 (2H, m), 3.17 (2H, m), 2.23 (2H, m), 2.09
(3H, s), 1.82 (2H, m),
1.20 (6H, d).
Example 168
[0666] 5-Chloro-2-{444-(2-isopropy1-5-methy1-4-tetrazol-1-yl-phenoxymethyl)-
thiazol-2-y1]-
piperidin-l-y1 }-pyrimidine fNyN
0
CI --N NN
N=KI
[0667] IIINMR (CDC13): 6 8.73 (1H, s), 8.20 (2H, s), 7.21 (1H, s), 7.09 (1H,
s), 6.90 (1H, s),
5.24 (2H, s), 4.78 (2H, m), 3.35 (1H, m), 3.28 (1H, m), 3.07 (2H, m), 2.19
(2H, m), 2.09 (3H, s),
1.79 (2H, m), 1.20 (6H, d).
Example 169
[0668] 5-Ethy1-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-oxazol-2-A-piperidin-l-
y1 }-
pyrimidine
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0 \
N 0 II
N 1
N
[0669] 11-1NMR (CDC13): 6 8.91 (1H, s), 8.18 (2H, s), 7.65 (1H, s), 7.60 (2H,
m), 7.15 (2H, m),
5.03 (2H, s), 4.69 (2H, m), 3.10 (3H, m), 2.44 (2H, q), 2.14 (2H, m), 1.86
(2H, m), 1.19 (3H, t).
Example 170
[0670] 5-Ethy1-2-{444-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-oxazol-2-A-
piperidin-1-
y1}-pyrimidine
N 0
N
I
[0671] 11-1NMR (CDC13): 6 8.93 (1H, s), 8.17 (2H, s), 7.67 (1H, s), 7.50 (1H,
m), 7.41 (1H, m),
7.29 (1H, m), 5.11 (2H, s), 4.67 (2H, m), 3.08 (3H, m), 2.45 (2H, q), 2.12
(2H, m), 1.84 (2H, m),
1.18 (3H, t).
Example 171
[0672] 2-{444-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
l-y1}-5-
trifluoromethyl-pyrimidine
-L
NO"N NN
1\1=-KI
F3C N
[0673] 1-14 NMR (CDC13): 6 8.91 (1H, s), 8.49 (2H, s), 7.52 (1H, d, J= 7.6
Hz), 7.41 (1H, d, J
= 7.6 Hz), 7.32 (1H, s), 7.29 (1H, m), 5.32 (2H, s), 4.95 (2H, m), 3.37 (1H,
m), 3.15 (2H, m),
2.24 (2H, m), 1.81 (2H, m).
Example 172
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[0674] 5-Decy1-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
l-y1}-
pyrimidine
NI 0-L/C)= N NrN
y-N
µN=K1
n-C101-121N
[0675] IIINMR (DMSO-d6): 6 9.97 (1H, s), 8.21 (2H, s), 7.80 (2H, d, J= 8.8
Hz), 7.65 (1H,
s), 7.28 (2H, d, J= 8.8 Hz), 5.20 (2H, s), 4.66 (2H, m), 3.32 (1H, m), 3.01
(2H, m), 2.37 (2H,
m), 2.09 (2H, m), 1.60 (2H, m), 1.45 (2H, m), 1.21 (14H, m), 0.82 (3H, m).
Example 173
[0676] 6-Methy1-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
l-y1}-
pyrimidine-4-carboxylic acid methyl ester
Q--N
Me02C
[0677] 1-1-1 NMR (DMSO-d6): 6 9.97 (1H, s), 7.80 (2H, d, J= 8.8 Hz), 7.66 (1H,
s), 7.28 (2H,
d, J= 8.8 Hz), 7.01 (1H, s), 5.21 (2H, s), 4.76 (2H, m), 3.84 (3H, s), 3.33
(1H, m), 3.06 (2H, m),
2.36 (3H, s), 2.14 (2H, m), 1.61 (2H, m).
Example 174
[0678] 4-Chloro-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
1-y1}-
pyrimidine
1110
N c NryN
µN=KN1
---N
CI
[0679] 1H NMR (CDC13): 6 8.91 (1H, s), 8.15 (1H, d, J= 5.2 Hz), 7.60 (2H, d,
J= 8.8 Hz),
7.25 (1H, s), 7.16 (2H, d, J= 8.8 Hz), 6.49 (1H, d, J= 5.2 Hz), 5.22 (2H, s),
4.85 (2H, m), 3.30
(1H, m), 3.07 (2H, m), 2.21 (2H, m), 1.80 (2H, m).
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Example 175
[0680] 2-Chloro-4-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
l-y1}-
pyrimidine
N¨LO
NrN
NrN h1=KI
CI
[0681] 111 NMR (CDC13): 6 8.90 (1H, s), 8.05 (1H, d, J= 6.4 Hz), 7.61 (2H, d,
J= 8.8 Hz),
7.28 (1H, s), 7.17 (2H, d, J= 8.8 Hz), 6.46 (1H, d, J= 6.4 Hz), 5.23 (2H, s),
4.45 (2H, m), 3.35
(1H, m), 3.15 (2H, m), 2.27 (2H, m), 1.85 (2H, m).
Example 176
[0682] 6-Methy1-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
l-y1}-
pyrimidine-4-carboxylic acid
Me Nyr\tia.4¨LO 110
N NrN
µN=1\1
---N
HOOC
[0683] IIINMR (DMSO-d6): 6 13.3 (1H, br), 9.97 (1H, s), 7.80 (2H, d, J= 8.8
Hz), 7.66 (1H,
s), 7.28 (2H, d, J= 8.8 Hz), 6.98 (1H, s), 5.21 (2H, s), 4.79 (2H, m), 3.34
(1H, m), 3.05 (2H, m),
2.35 (3H, s), 2.13 (2H, m), 1.62 (2H, m).
Example 177
[0684] 5-Chloro-4,6-difluoro-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-
y1]-piperidin-
l-y1}-pyrimidine
N NiaN¨LO
-kN NrN
1\1=KI
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[0685] 1H NMR (CDC13): 6 8.91 (1H, s), 7.61 (2H, d, J= 8.8 Hz), 7.27 (1H, s),
7.16 (2H, d, J
= 8.8 Hz), 5.23 (2H, s), 4.69 (2H, m), 3.32 (1H, m), 3.10 (2H, m), 2.23 (2H,
m), 1.80 (2H, m).
Example 178
[0686] 4-Fluoro-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-A-piperidin-l-
y1}-
pyrimidine
---or\ µS¨c, =
NvN
1\1=KI
N
[0687] IIINMR (DMSO-d6): 6 9.97 (1H, s), 8.41 (1H, m), 7.80 (2H, d, J= 8.0
Hz), 7.66 (1H,
s), 7.28 (2H, d, J= 8.0 Hz), 6.34 (1H, m), 5.20 (2H, s), 4.60 (2H, m), 3.32
(1H, m), 3.10 (2H,
m), 2.11 (2H, m), 1.61 (2H, m).
Example 179
[0688] 2-Fluoro-4-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-A-piperidin-l-
y1}-
pyrimidine
=NrN
Nr.N
[0689] IIINMR (DMSO-d6): 6 9.98 (1H, s), 8.08 (1H, m), 7.80 (2H, d, J= 9.2
Hz), 7.67 (1H,
s), 7.28 (2H, d, J= 9.2 Hz), 6.84 (1H, m), 5.20 (2H, s), 4.40 (2H, m), 3.40
(1H, m), 3.14 (2H,
m), 2.13 (2H, m), 1.63 (2H, m).
Example 180
[0690] 2-{444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-l-y1}-
thiazole-5-
carboxylic acid ethyl ester
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=NN
1\1=KI
[0691] IIINMR (DMSO-d6): 6 9.97 (1H, s), 7.84 (1H, m), 7.80 (2H, d, J= 9.0
Hz), 7.68 (1H,
s), 7.28 (2H, d, J= 9.0 Hz), 5.21 (2H, s), 4.19 (2H, t, J= 7.20 Hz), 4.03 (2H,
m), 3.35 (3H, m),
2.15 (2H, m), 1.75 (2H, m), 1.23 (3H, t, J= 7.20 Hz).
Example 181
[0692] 4-Imidazol-1-y1-6-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidin-l-y1}-
pyrimidine
110
,9-10'cN
1\1=N
[0693] 1H NMR (DMSO-d6): 6 9.98 (1H, s), 8.59 (1H, s), 8.43 (1H, s), 8.01 (1H,
d, J= 1.2
Hz), 7.81 (2H, d, J= 8.8 Hz), 7.67 (1H, s), 7.27 (2H, d, J= 8.8 Hz), 7.14 (1H,
s), 7.10 (1H, d, J
= 1.2 Hz), 5.20 (2H, s), 4.61 (2H, m), 3.40 (1H, m), 3.15 (2H, m), 2.15 (2H,
m), 1.66 (2H, m).
Example 182
[0694] 5-Ethy1-2-{444-(6-tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-y1]-
piperidin-l-y1}-
pyrimidine.
-N
oi
N N
N
Nz-z:N/
[0695] IIINMR (CDC13): 6 9.44 (1H, s), 8.28 (1H, d, J= 3.0 Hz), 8.2 (2H, s),
8.02, (1H, d, J=
8.8 Hz), 7.58 (1H, dd, J= 8.8 Hz, 3.0 Hz), 7.27 (1H, s), 5.27 (2H, s), 4.82-
4.85 (2H,m), 3.22-
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3.35 (1H,m), 3.0-3.1, (2H, m), 2.47 (2H, q, J= 7.2 Hz), 2.2-2.23 (2H, m), 1.76-
1.86 (2H, m),
1.19 (3H, t, J= 7.2 Hz).
Example 183
[0696] 5-Methy1-2-{444-(6-tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-y1]-
piperidin-1-
y1}-pyrimidine
N¨\)
N N
0
--N
N
N
[0697] 1-14NMR (DMSO-d6): 6 10.07 (1H, s), 8.42 (1H, d, J= 3.0 Hz), 8.21 (2H,
s), 7.99 (1H,
d, J= 9.2 Hz), 7.86 (1H, dd, J= 9.2 Hz, 3.0 Hz), 7.70 (1H, s), 5.30 (2H, s),
4.62 (2H, m), 3.56-
3.60 (1H, m), 2.98-3.04 (2H, m), 2.06 (3H, s), 1.72-1.76 (2H, m), 1.59 (2H,
m).
Example 184
[0698] 5-Chloro-2-{444-(6-tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-y1]-
piperidin-1-
y1}-pyrimidine.
N S,
I
-N __________________________________ N-Th
0
I
N
I N
N-
-N
[0699] 1-14NMR (CDC13) 6 9.44 (1H, s), 8.28 (1H, d, J= 3.0 Hz), 8.23 (2H, s),
8.02 (1H, d, J=
9.0 Hz), 7.58 (1H, dd, J= 9.0 Hz, 3.0 Hz), 7.28 (1H, s), 5.27 (2H, s), 4.8-
4.83 (2H, m), 3.22-
3.38 (1H, m), 3.04-3.11 (2H, m), 2.20-2.23 (2H, m), 1.80 (2H, m)
Example 185
[0700] 2-{444-(6-Tetrazol-1-yl-pyridin-3-yloxymethyl)-thiazol-2-y1]-piperidin-
1-y1}-5-
trifluoromethyl-pyrimidine.
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FoD
N
N N
N
N '
N
[0701] 1-1-1NMR (DMSO-d6): 6 10.07 (1H, s), 8.68 (2H, s), 8.42 (1H, d, J= 3.0
Hz), 7.99 (1H,
d, J= 9.2 Hz), 7.86 (1H, dd, J= 9.2 Hz, 3.0 Hz), 7.72 (1H, s), 5.73 (2H, s),
4.74-4.77 (2H, m),
3.37-3.43 (1H, m), 3.15-3.21 (2H, m), 2.12-2.16 (2H, m), 1.59-1.68 (2H, m).
Example 186
[0702] 3-Chloro-6-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
l-y1}-
pyridazine
N=N
0
N
[0703] 1-1-1NMR (CDC13): 6 8.91 (1H, s), 7.61 (2H, d, J= 9.0 Hz), 7.26 (1H,
s), 7.22 (1H, d, J
= 9.6 Hz), 7.17 (2H, d, J= 9.0 Hz), 6.95 (1H, d, J= 9.6 Hz), 5.23 (2H, s),
4.43-4.47 (2H, m),
3.31-3.37 (1H, m), 3.12-3.19 (2H, m), 2.25-2.28 (2H, m), 1.90 (2H, m).
Example 187
[0704] 2-Tetrazol-1-y1-5-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidin-l-y1}-
pyrazine
N
N=zziN
0
N
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[0705] 1-14NMR (DMSO-d6): 6 9.97 (2H, s), 8.67 (1H, s), 8.37 (1H, s), 7.80
(2H, d, J = 8.8
Hz), 7.67 (1H, s), 7.28 (2H, d, J= 8.8 Hz), 5.21 (2H, s), 4.50-4.53 (2H, m),
3.38-3.44 (1H, m),
3.17-3.23 (2H, m), 2.15-2.18 (2H, m), 1.69-1.77 (2H, m).
Example 188
[0706] {241-(5-Ethyl-pyrimidin-2-y1)-piperidin-4-y1}-thiazol-4-ylmethyl }-(6-
fluoro-pyridin-
3-y1)-amine
F
I I
[0707] 1-1-1 NMR (CDC13): 6 8.19 (2H, s), 7.58-7.62 (1H, m), 7.05-7.10 (1H,
m), 7.01 (1H, s),
6.75 (1H, dd, J= 8.4 Hz, 2.8 Hz), 4.81-4.85 (2H, m), 4.40 (2H, d, J= 5.2 Hz),
4.29 (1H, br s),
3.23-3.29 (1H, m), 3.00-3.06 (2H, m), 2.47 (2H, q, J= 7.6 Hz), 2.18-2.20 (2H,
m), 1.79 (2H, m),
1.20 (3H, t, J = 7.6 Hz).
Example 189
[0708] 2-{444-(2,6-Difluoro-4-methanesulfonyl-phenoxymethyl)-thiazol-2-y1}-
piperidin-1-
y1}-5-ethyl-pyrimidine
S1,_zo
Ny
S,
N
N
[0709] 1-14 NMR (CDC13): 6 8.19 (2H, s,), 7.51 (2H, d), 7.25 (1H, s), 5.40
(2H, s), 4.82 (2H,
m), 3.30 (1H, m), 3.06 (3H, s), 3.03 (2H, m), 2.48 (2H, q), 2.15 (2H, m), 1.74
(2H, m), 1.20 (3H,
Example 190
[0710] 5-Buty1-2-{444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1}-piperidin-
l-y1}-
pyrimidine
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N
¨N
N¨Ns
[0711] 1H Wit (CDC13): 6 8.92 (1H, s), 8.17 (2H, s), 7.62 (2H, m), 7.25 (1H,
s), 7.17 (2H,
m), 5.24 (2H, s), 4.83 (2H, m), 3.30 (1H, m), 3.04 (2H, m), 2.42 (2H, t), 2.23
(2H, m), 1.84 (2H,
m), 1.52 (2H, m), 1.34 (2H, m), 0.92 (3H, m).
Example 191
[0712] 4-(4-{241-(5-Ethyl-pyrimidin-2-y1)-piperidin-4-A-thiazol-4-ylmethoxy}-
pheny1)-
morpholine
¨N ________________________________
NTh
[0713] 1H NMIt (CDC13): 6 8.18 (2H, s), 7.19 (1H, s), 6.92 (4H, m), 5.12 (2H,
s), 4.84 (2H,
m), 3.86 (4H, br), 3.30 (1H, m), 3.05 (6H, m), 2.46 (2H, q), 2.21 (2H, m),
1.78 (2H, m), 1.19
(3H, t).
Example 192
[0714] 5-Nitro-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
l-y1 -
pyrimidine
=
\o /N
N
1\1=N
N N
Ly
r N
02N
[0715] 1H Wit (DMSO-d6): 6 9.91 (1H, s), 9.11 (2H, s), 7.83 (2H, d, J= 8.8
Hz), 7.68 (1H,
s), 7.25 (2H, d, J = 8.8 Hz), 5.22 (2H, s), 4.81 (2H, m), 3.39 (1H, m), 3.31
(2H, m), 2.23 (2H, s),
1.68 (2H, m).
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Example 193
[0716] 3'-Chloro-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-5'-
trifluoromethy1-
3,4,5,6-tetrahydro-2H-[1,21bipyridinyl
0 /I N
N N
F Z CI
[0717] 11-1NMR (CDC13): 6 8.91 (1H, s), 8.39 (1H, s), 7.76 (1H, s), 7.61 (2H,
m), 7.25 (1H, s),
7.18 (2H, m), 5.24 (2H, s), 4.16 (2H, m), 3.26 (1H, m), 3.06 (2H, m), 2.25
(2H, m), 2.01 (2H, m).
Example 194
[0718] 3'-Chloro-444-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-5'-

trifluoromethy1-3,4,5,6-tetrahydro-2H-[1,21bipyridinyl
(D7N/ \13=1\1/1\i,
N N 1\1=N
F
CI
[0719] 1H NMR (CDC13): 6 8.94 (1H, s), 8.38 (1H, s), 7.75 (1H, s), 7.53 (1H,
m), 7.40 (1H, m),
7.31 (1H, s), 7.25 (1H, m), 5.31 (2H, s), 4.15 (2H, d), 3.25 (1H, m), 3.09
(2H, m), 2.23 (2H, d),
1.99 (2H, m).
Example 195
[0720] 5-Chloro-2-{444-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidin-1-
y1 -pyrimidine
ci
YN 0 ao N
'
'N'
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[0721] 1H NIVIR (CDC13): 6 8.96 (1H, s), 8.20 (2H, s), 7.52 (1H, m), 7.40 (1H,
m), 7.28 (1H, s),
7.25 (1H, m), 5.28 (2H, s), 4.78 (2H, m), 3.30 (1H, m), 3.07 (2H, m), 2.20
(2H, m), 1.79 (2H, m).
Example 196
[0722] 3',5'-Dichloro-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
3,4,5,6-tetrahydro-
2H41,2'Thipyridinyl
/N
\ N
CI
CI
[0723] 1H Wit (DMSO-d6): 6 9.98 (1H, s), 8.26 (1H, s), 8.03 (1H, s), 7.81 (2H,
d), 7.67 (1H,
s), 7.29 (2H, d), 5.21 (2H, s), 3.79 (2H, m), 3.24 (1H, m), 2.97 (2H, m), 2.14
(2H, m), 1.84 (2H,
m).
Example 197
[0724] 3'-Chloro-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-3,4,5,6-
tetrahydro-2H-
[1,2']bipyridiny1-5'-carboxylic acid ethyl ester
¨
N N
0 CI
[0725] 1H Wit (CDC13): 6 8.92 (1H, s), 8.74 (1H, s), 8.11 (1H, s), 7.61 (2H,
d), 7.25 (1H, s),
7.17 (2H, d), 5.23 (2H, s), 4.37 (2H, m), 4.22 (2H, m), 3.31 (1H, m), 3.08
(2H, m) 2.26 (2H, m),
1.98 (2H, m), 1.38 (3H, m).
Example 198
[0726] 5'-Chloro-4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-3,4,5,6-
tetrahydro-2H-
[1,2']bipyridiny1-3'-carboxylic acid methyl ester
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(D N
N N
0
CI
0
[0727] 1-14NMR (CDC13): 6 8.91 (1H, s), 8.20 (1H, s), 7.99 (1H, s), 7.61 (2H,
d), 7.25 (1H, s),
7.16 (2H, d), 5.21 (2H, s), 3.91 (2H, m), 3.88 (3H, s), 3.28 (1H, m), 3.08
(2H, m), 2.20 (2H, m),
1.93 (2H, m).
Example 199
[0728] 5-Ethy1-2-{3-methyl-444-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1}-
piperidin-1-
y1}-pyrimidine
S¨\\
NyN
1\1=KI
[0729] 1H Wit (CDC13): 6 8.90(1H, s), 8.18 (2H), 7.60 (2H, m), 7.25 (1H, s),
7.17 (2H, m),
5.26 (2H), 4.89-4.51 (2H, m), 3.49-3.20 (2H, m), 2.92 (1H, m), 2.65-2.45 (1H,
m), 2.45 (2H, m),
2.17-1.81 (2H, m), 1.20 (3H, m), 0.82-0.92 (3H).
Example 200
[0730] 5-Ethy1-2-{444-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-3-
methyl-
piperidin-l-y1}-pyrimidine
0NN
IR N/N
N
[0731] 1-14NMR (CDC13): 6 8.93 (1H, s), 8.17 (2H), 7.52-7.25 (4H, m), 5.32
(2H), 4.84-4.46
(2H, m), 3.47-3.22 (2H, m), 2.91 (1H, m), 2.62-2.43 (1H, m), 2.42 (2H, m),
2.07 (2H, m), 1.18
(3H, m), 0.90-0.79 (3H, m).
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Example 201
[0732] 5-Chloro-2-{444-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
3-methyl-
piperidin-1-y1}-pyrimidine
N N
CI
[0733] 1-14 NMR (CDC13): 6 8.93 (1H, s), 8.19(2H), 7.52-7.25 (4H, m), 5.29
(2H), 4.82-4.51
(2H, m), 3.46-3.21 (2H, m), 2.95 (1H, m), 2.64-2.42 (1H, m), 2.02 (2H, m),
0.90-0.78 (3H, m).
Example 202
[0734] 2-{444-(2-Fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-3-methyl-
piperidin-1-
y1}-5-trifluoromethyl-pyrimidine
N C--"N 411 N N
,
[0735] 1-14 NMR (CDC13): 6 8.94 (1H, s), 8.47 (2H), 7.53-7.27 (4H, m), 5.34
(2H), 5.02-4.62
(2H, m), 3.52-2.97 (3H, m), 2.73-2.47 (1H, m), 2.17-2.01 (2H, m), 0.94-0.78
(3H, m).
Example 203
[0736] 5-Ethy1-2-{444-(4-methanesulfonyl-benzyloxymethyl)-thiazol-2-y1]-
piperidin-l-y1}-
pyrimidine
NrN
\
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[0737] 1-14 NMIt (CDC13): 6 8.17 (2H, s), 7.92 (2H, d, J= 8.8 Hz ), 7.58 (2H,
d, J= 8.8 Hz),
7.13 (1H, s), 4.83 (2H, m), 4.71 (2H, s), 4.66 (2H, s), 3.27 (1H, m), 3.03
(3H, s), 2.98 (2H, m),
2.46 (2H, m), 2.19 (2H, m), 1.76 (2H, m), 1.19 (3H, m).
Example 204
[0738] 5-Fluoro-2-{444-(2-fluoro-4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidin-1-
y1}-pyrimidine
Ni 11100
N N
Ny N
N= N
I
F
[0739] 1-1-1 NMR (CDC13): 6 8.91 (1H, s), 8.21 (2H, s), 7.52 (1H, m), 7.41
(1H, m), 7.27 (1H,
m), 7.25 (1H, s), 5.31 (2H, s), 4.76 (2H, m), 3.28 (1H, m), 3.06 (2H, m), 2.20
(2H, m), 1.81 (2H,
Example 205
/N
N
fNNN
F3C N
[0740] 1-14 NMIt (CDC13): 6 8.91 (1H, s), 8.49 (2H, s), 7.61 (2H, d), 7.27(1H,
s), 7.17 (2H, d),
5.24 (2H, s), 4.96 (2H, m), 3.38 (1H, m), 3.14 (2H, m), 2.26 (2H, m), 1.82(2H,
m).
Example 206
[0741] 4444 [(4-Methanesulfonyl-phenyl)-methyl-amino]-methyl -thiazol-2-y1)-
piperidine-1-
carboxylic acid tert-butyl ester
N N=
N
>10
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[0742] 4-{4-[(4-Methanesulfonyl-phenylamino)-methy1]-thiazol-2-y1} -piperidine-
l-carboxylic
acid tert-butyl ester (Example 138) (0.10 mmol) was dissolved in DMF (2 mL)
and NaH (2 eq.)
was added in a single portion at room temperature. The reaction was stirred
for 30 minutes and
methyl iodide (10 eq.) was added. After stirring for 3 hours, the reaction was
quenched with
water and extracted with Et0Ac. The organic layer was washed with brine, dried
over sodium
sulfate, filtered and concentrated in vacuo. Purification of the residue by
silica gel
chromatography (Hexanes/Et0Ac 1:1) provided the expected product. lEINMR
(CDC13): 6 7.73
(2H, m), 6.78 (2H, m), 6.76 (1H, s), 4.70 (2H, s), 4.20 (2H, br), 3.19 (3H,
s), 3.12 (1H, m), 3.01
(3H, s), 2.87 (2H, m), 2.07 (2H, m), 1.80 (2H, m), 1.47 (9H, s).
Example 207
[0743] {241-(5-Ethyl-pyrimidin-2-y1)-piperidin-4-y1]-thiazol-4-ylmethyl -(2-
fluoro-4-
methanesulfonyl-pheny1)-methyl-amine
0
fNNSH
411
N N
rGN
[0744] Example 207 was synthesized in a manner analogous to Example 206
utilizing {241-
(5-Ethyl-pyrimidin-2-y1)-piperidin-4-y1]-thiazol-4-ylmethyl -(2-fluoro-4-
methanesulfonyl-
pheny1)-amine (Example 141) as the starting material. lEINMR (CDC13): 6 8.19
(2H, s), 7.47-
7.57 (2H, m), 6.94 (1H, s), 6.91 (1H, m), 4.80 (2H, m), 4.62 (2H, s), 3.24
(1H, m), 3.09 (3H, s),
3.03 (3H, s), 3.00 (2H, m), 2.47 (2H, m), 2.17 (2H, m), 1.74 (2H, m), 1.19
(3H, t).
Example 208
[0745] 4-[4-(2-Methylsulfanyl-pyrimidin-5-yloxymethyl)-thiazol-2-y1]-
piperidine-1-
carboxylic acid tert-butyl ester
S
0
N/ S
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[0746] Example 208 was prepared from 4-(4-Chloromethyl-thiazol-2-y1)-
piperidine-1-
carboxylic acid tert-butyl ester (Intermediate 1) and 2-Methylsulfanyl-
pyrimidin-5-ol in a
manner similar to that described in Example 1. 1EINMR (CDC13): 6 8.35 (2H, s),
7.23 (1H, s),
5.19 (2H, s), 4.22 (2H, m), 3.16 (1H, m), 2.87 (2H, m), 2.55 (3H, s), 2.10
(2H, m), 1.71 (2H, m),
1.46 (9H, s).
Example 209
[0747] 444-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidine-1-
carboxylic acid allyl
ester
S
OyN 111
N
NN
[0748] Example 209 was prepared from 444-(4-Tetrazol-1-yl-phenoxymethyl)-
thiazol-2-y1]-
piperidine (Intermediate 4) and allyl chloroformate in a manner similar to
that described in
Example 22. 1H NMR (CDC13): 6 8.96 (1H, s), 7.63 (2H, m), 7.20 (1H, s), 7.18
(2H, m), 5.96
(1H, m), 5.31 (1H, m), 5.22 (3H, m), 4.61 (2H, m), 4.29 (2H, m), 3.21 (1H, m),
2.97 (2H, m),
2.15 (2H, m), 1.78 (2H, m).
Example 210
[0749] 2-{4[4-Methy1-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-piperidin-
l-y1 -5-
trifluoromethyl-pyrimidine
r 2N
[0750] Step 1: 444-Methy1-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidine
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I :1\1
N-N'
H1 NNN
[0751] A solution of 4-[4-Methy1-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-
y1]-piperidine-
1-carboxylic acid tert-butyl ester (Example 93) (500 mg, 1.10 mmol) in
dichloromethane (5
mL) was treated with 1.5 mL of 4 N HC1 in dioxane. The resulting solution was
stirred at room
temperature for 5 hours and all the solvent were removed in vacuo to afford
the desired product
as an HC1 salt.
[0752] Step 2: 2-{444-Methy1-5-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-y1]-
piperidin-1-
y1 -5-trifluoromethyl-pyrimidine
r 2N
-NNTiC
[0753] This compound was prepared from 4-[4-Methy1-5-(4-tetrazol-1-yl-
phenoxymethyl)-
thiazol-2-y1]-piperidine hydrochloride in a similar manner as described in
Example 47. 1-1-1
NMR (CDC13): 6 8.94 (1H, s), 8.49 (2H, s), 7.64 (2H, m), 7.14 (2H, m), 5.20
(2H, s), 4.95 (2H,
m), 3.27 (1H, m), 3.13 (2H, m), 2.46 (3H, s), 2.21 (2H, m), 1.77 (2H, m).
Biological Example 1
[0754] A compound of Formula (I) is evaluated in a porcine model of short
bowel syndrome
(see, e.g., Surgery, 2011 Aug;150(2):217-23.). Functional assessment (e.g.,
changes in body
weight and/or nutrient uptake), morphological assessment (e.g., histology),
and molecular
assessment (e.g., measurement of peptidyl biomarkers) are performed.
Biological Example 2
[0755] A composition comprising a compound of Formula (I) and a DPP-IV
inhibitor is
evaluated in a porcine model of short bowel syndrome, as described in
Biological Example 1.
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Biological Example 3
[0756] A composition comprising a compound of Formula (I), a DPP-IV inhibitor,
and
metformin is evaluated in a porcine model of short bowel syndrome, as
described in Biological
Example 1.
Biological Example 4
[0757] A compound of Formula (I) is evaluated in a murine model of
inflammatory bowel
disease (see, e.g., Prog Mol Biol Transl Sci., 2012;105:263-320). Histologic
analysis is
performed.
Biological Example 5
[0758] A composition comprising a compound of Formula (I) and a DPP-IV
inhibitor is
evaluated in a murine model of inflammatory bowel disease, as described in
Biological Example
4.
Biological Example 6
[0759] A composition comprising a compound of Formula (I), a DPP-IV inhibitor,
and
metformin is evaluated in a murine model of inflammatory bowel disease, as
described in
Biological Example 4.
Biological Example 7
[0760] A compound of Formula (I) is evaluated in a clinical study involving
human volunteers
with short bowel syndrome. The improvement of intestinal absoprtion is
assessed.
Biological Example 8
[0761] A composition comprising a compound of Formula (I) and a DPP-IV
inhibitor is
evaluated in human volunteers with short bowel syndrome, as described in
Biological Example
7.
Biological Example 9
[0762] A composition comprising a compound of Formula (I), a DPP-IV inhibitor,
and
metformin is evaluated in human volunteers with short bowel syndrome, as
described in
Biological Example 7.
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Biological Example 10
[0763] A compound of Formula (I) is evaluated in a clinical study involving
human volunteers
with inflammatory bowel disease. Partial or complete response is measured.
Biological Example 11
[0764] A composition comprising a compound of Formula (I) and a DPP-IV
inhibitor is
evaluated in human volunteers with inflammatory bowel disease, as described in
Biological
Example 10.
Biological Example 12
[0765] A composition comprising a compound of Formula (I), a DPP-IV inhibitor,
and
metformin is evaluated in human volunteers with inflammatory bowel disease, as
described in
Biological Example 10.
[0766] All patents, patent applications, publications and presentations
referred to herein are
incorporated by reference in their entirety. Any conflict between any
reference cited herein and
the teaching of this specification is to be resolved in favor of the latter.
Similarly, any conflict
between an art-recognized definition of a word or phrase and a definition of
the word or phrase
as provided in this specification is to be resolved in favor of the latter.
[0767] While certain embodiments have been illustrated and described, it
should be
understood that changes and modifications can be made therein in accordance
with ordinary skill
in the art without departing from the technology in its broader aspects as
defined in the
following claims.
[0768] The embodiments, illustratively described herein may suitably be
practiced in the
absence of any element or elements, limitation or limitations, not
specifically disclosed herein.
Thus, for example, the terms "comprising," "including," "containing," etc.
shall be read
expansively and without limitation. Additionally, the terms and expressions
employed herein
have been used as terms of description and not of limitation, and there is no
intention in the use
of such terms and expressions of excluding any equivalents of the features
shown and described
or portions thereof, but it is recognized that various modifications are
possible within the scope
of the claimed technology. Additionally, the phrase "consisting essentially
of' will be
understood to include those elements specifically recited and those additional
elements that do
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not materially affect the basic and novel characteristics of the claimed
technology. The phrase
"consisting of' excludes any element not specified.
[0769] The present disclosure is not to be limited in terms of the particular
embodiments
described in this application. Many modifications and variations can be made
without departing
from its spirit and scope, as will be apparent to those skilled in the art.
Functionally equivalent
methods and compositions within the scope of the disclosure, in addition to
those enumerated
herein, will be apparent to those skilled in the art from the foregoing
descriptions. Such
modifications and variations are intended to fall within the scope of the
appended claims. The
present disclosure is to be limited only by the terms of the appended claims,
along with the full
scope of equivalents to which such claims are entitled. It is also to be
understood that the
terminology used herein is for the purpose of describing particular
embodiments only, and is not
intended to be limiting.
[0770] In addition, where features or aspects of the disclosure are described
in terms of
Markush groups, those skilled in the art will recognize that the disclosure is
also thereby
described in terms of any individual member or subgroup of members of the
Markush group.
[0771] As will be understood by one skilled in the art, for any and all
purposes, particularly in
terms of providing a written description, all ranges disclosed herein also
encompass any and all
possible subranges and combinations of subranges thereof. Any listed range can
be easily
recognized as sufficiently describing and enabling the same range being broken
down into at
least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting
example, each range
discussed herein can be readily broken down into a lower third, middle third
and upper third, etc.
As will also be understood by one skilled in the art all language such as "up
to," "at least,"
"greater than," "less than," and the like, include the number recited and
refer to ranges which
can be subsequently broken down into subranges as discussed above. Finally, as
will be
understood by one skilled in the art, a range includes each individual member.
[0772] Other embodiments are set forth in the following claims.
163